UA119541C2 - Anti-folr1 immunoconjugate dosing regimens - Google Patents

Abstract

The invention relates to a method of treating a human patient having FOLR1-expressing cancer, comprising administering to the patient a composition comprising an immunoconjugate that binds to the FOLR1 polypeptide, and the immunoconjugate contains an average of 3-4 DM4-maytansinoids per antibody , in which DM4-maytansinoids are connected to the antibody by sulfo-SPDB, and the immunoconjugate is administered at a dose of 6 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIBW) of the patient once every three weeks. The invention also relates to the use of an immunoconjugate in the manufacture of a medicament for the treatment of FOLR1-expressing cancer.

Description

body weight (AIVMU) of the patient once every three weeks.

The invention also relates to the use of an immunoconjugate in the manufacture of a medicinal product for the treatment of KII-expressing cancer.

TECHNICAL FIELD

ИО00О1| The field of technology, in general, refers to methods of administration of immunoconjugates of anti-

AI AIs for the treatment of diseases such as cancer. The methods suggest administration schedules that minimize unwanted side effects.

TECHNICAL LEVEL

I0002) Cancer is one of the leading causes of mortality in the developed world, and only in

In the United States, more than one million people are diagnosed with cancer, with 500,000 deaths annually. According to general estimates, more than 1 in 3 men will develop some form of cancer during their lifetime. There are more than 200 different types of cancer, four of which - breast, lung, colon and rectal, and prostate - account for more than half of all new cases (Etptaiyi ei ai., 2003, Sapseg 4). Siip. 53:5-26).

I0003)| Folic acid receptor 1 (FOL), also known as folate receptor-alpha or folate-binding protein, is an M-glycosylated protein expressed on the plasma membrane of cells. ROIMK1 has a high affinity for folic acid and some reduced derivatives of folic acid. BOI K1 mediates the delivery of physiological folate, 5-methyltetrahydrofolate, into the interior of cells. (0004) ROI K1 is overexpressed in the vast majority of ovarian cancers, as well as in many cancers of the uterus, endometrium, pancreas, kidney, lung, and breast, while expression of ROI KI in normal tissues is restricted to the apical membrane of epithelial cells in proximal renal tubules, alveolar pneumocytes of the lung, urinary bladder, testicles, choroid plexus and thyroid gland (UUueytap 50, ейі ай., Sapseg

Ves 52: 3396-3401 (1992); Apiyuopu AS, Appi Nem Myik 16: 501-521 (1996); Kaiyi KE, eiyi aI. Supesoi!

Opsoi 108: 619-626 (2008)). This nature of the expression of ROI K1 makes it a desirable target for

EOY of B1-directed cancer therapy.

ИО005| Because ovarian cancer is usually asymptomatic until late stage, it is often diagnosed at a late stage with a poor prognosis if treated with currently available techniques, usually chemotherapy drugs after surgical removal (mop Sgyepidep Meyi ai!., Sapseg 112: 2221-2227 (2008); Aupap A evy a!., At ) OBziei

From Supesoi! 196: 81 e81-86 (2007); Nagtu UM eyi a!., OB5iei Supesoi Zygm 64: 548-560 (2009)). Thus, there is a clear unmet medical need for more effective ovarian cancer therapy. (0006) Antibodies are increasingly recognized as a promising treatment for such cancers.

In addition, immunoconjugates containing an antibody conjugated to another compound, such as a cytotoxin, are also being studied as a potential therapy. In particular, immunoconjugates containing maytansinoids, which are antifungal and antitumor agents of plant origin, have shown some beneficial activity. The isolation of three loop macrolides from ethanolic extracts of Mauiepiv5 omaiya5 and Mauiepiv5 rispapapiya was reported for the first time

Z. M. Kirspap et al., and they are the object of the invention in accordance with the US patent No. 3896111, together with the demonstration of their antileukemic effects in mouse models in the dose range of μg/kg.

However, maytansinoids have unacceptable toxicity, causing both central and peripheral neuropathy and side effects: notably nausea, vomiting, diarrhea, elevated liver function tests, and, less commonly, weakness and lethargy. Such general toxicity is reduced to some extent by conjugation of maytansinoids with antibodies, since the antibody conjugate has toxicity that is several orders of magnitude lower for antigen-negative cells than for antigen-positive cells. However, immunoconjugates containing maytansinoids are still associated with unacceptable levels of unwanted side effects. For example, in animals injected with high doses of anti-POi K1 immunoconjugates containing maytansinoid, eye toxicity was detected. The cause of this toxicity, such as whether it is related to Stach or AOS, is unknown. As a result, there is still a need to identify specific schemes for the administration of anti-ROI K1 immunoconjugates, which are therapeutically effective for humans, but which allow avoiding side effects.

BRIEF DESCRIPTION OF THE ESSENCE OF THE INVENTION

I0007| This document proposes methods of administration of the anti-ROI K1 immunoconjugate in a therapeutically effective administration scheme that minimizes unwanted side effects. As described in more detail below, administration of the same dose of anti-ROI K1 immunoconjugate to different patients results in significant variation in the pharmacokinetics of the immunoconjugate (eg, Stach and AOS). The authors of the present invention have found, and the experiments presented herein demonstrate, that ophthalmic toxicity correlates with high Stach and high initial AC.

However, a high Stach and an initial value of AOS are not required to achieve efficiency. bo Accordingly, described herein are methods of treating a patient with cancer, comprising administering to the patient an effective dose of an immunoconjugate that binds to ROI CI, wherein the immunoconjugate is administered at a dose of from about 3.0 mg/kg to about 7 ,0 mg/kg, while kg of body weight is carried out to ideal body weight (IBW), dry body weight (I BWM), or adjusted ideal body weight (ASU or AIVWM). The abbreviations "ABU" and "AIVMUU" can be used interchangeably to indicate adjusted ideal body weight. In some variants of the implementation of the invention, kilograms lead to AIIVUM (ABU)). Also described herein are methods of treating a patient with cancer comprising administering to the patient an effective dose of an immunoconjugate that binds to BOI K1, wherein the immunoconjugate is administered once a week for three weeks in accordance with a four-week regimen (e.g., in 1, 8, and 15 days of the four-week regime). Also described herein are methods of treating a patient with cancer, comprising administering to the patient an effective dose of an immunoconjugate that binds to a BAI, wherein the immunoconjugate is administered at a dose of from about 1.0 mg/kg to about 7.0 mg/kg, while kg of body weight is brought to I VM, I VMU, or AIVUM (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen (for example, in 1, 8, ii 15 days of a four-week regime). Methods that are described in this document can lead to reduced toxicity, for example, ophthalmic toxicity.

ІІ000О8| In addition, described herein are methods of treating a patient with cancer, which include administering to the patient an effective dose of an immunoconjugate that binds to EOI KI, which differ in that the Stach and the initial value of AC, which lead to intoxication, are not exceeded. For example, in some embodiments of the invention, the introduction provides a Sevtakh of about 90-160 μg/ml and in some embodiments of the invention, the introduction provides a Stakh of about 110-160 μg/ml. In some variants of implementation of the invention, the introduction provides AOSo-ha no more than 2785 h-μg/ml. In some variants of the implementation of the invention, the introduction provides AOsCo-24 no more than 2741 h-μg/ml. In some embodiments of the invention, the introduction provides

ASHSo-ha no more than 2700 h-μg/ml. In some variants of implementation of the invention, the introduction provides Stakh no more than 160 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh no more than 150 μg/ml. 0009) In some variants of the implementation of the invention, the introduction provides AOSo-ha about 1000-3500 h-:μg/ml. In some variants of implementation of the invention, the introduction provides about AOSo-ha

From 1000-3000 h-mcg/ml. In some variants of the implementation of the invention, the introduction provides ASHcSO-2a about 1000-2785 h-μg/ml. In some embodiments of the invention, the introduction provides

ASHSo-ha is about 1000-2741 h-μg/ml. In some variants of the implementation of the invention, the introduction provides ASHSo-gi about 1000-2700 h.mcg / ml. In some variants of the implementation of the invention, the introduction provides AOSogy about 1000-2500 h-μg / ml. In some variants of implementation of the invention, the introduction provides AOsCo-2a4 no more than 1500-3500 h.mcg/ml. In some variants of implementation of the invention, the introduction provides AOSo-ha" no more than 1500-3000 h.mcg/ml. In some variants of implementation of the invention, the introduction provides AOSo-24" no more than 1500-2785 h-μg/ml.

In some variants of implementation of the invention, the introduction provides AOSo-ha no more than 1500-2741 h-μg/ml. In some variants of implementation of the invention, the introduction provides AOSo-g" not more than 1500-2700 h-μg/ml. In some variants of the implementation of the invention, the introduction provides ASHcSO-2a about 1500-2500 h-μg/ml. 0010) In some variants of implementation of the invention, the introduction provides Stakh 110-160 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh 110-150 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh 110-140 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh 120-160 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh of about 120-150 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh of about 120-140 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh 90-160 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh of about 90-150 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh of about 90-140 μg/ml. In some variants of the implementation of the invention, the introduction provides Stakh 100-160 μg/ml. In some variants of the implementation of the invention, the introduction provides Stakh of about 100-150 μg/ml. In some variants of implementation of the invention, the introduction provides Stakh of about 100-140 μg/ml. 0011) Immunoconjugate anti-ROI CI may contain a charged linker. In some variants of the implementation of the invention, the anti-ROI K1 immunoconjugate contains the pPiMom19 antibody, the sulfo-5ROV linker, and the maytansinoid OMA.

I0012| In some embodiments of the invention, the immunoconjugate contains an antibody or its antigen-binding fragment, which competitively inhibits the binding of an antibody with the sequences ZEO IYUO Mo: C and BEO IYU Me: 5 to ROI K1. In some embodiments of the invention, the antibody or its fragment contains the COM piMom19 (ie, ZEO IJU MO: 6-10 and 12 or 5EO IJU MO: 6-9, 11 and 12. In some variants of the invention, the antibody or its antigen-binding fragment contains a variable region of the sequence of PIMOM19 ( i.e., ZEO IUO Mo: C and 5). In some embodiments of the invention, antibodies or fragments do not contain the six SOCs of murine Mom19 (i.e., ZEO

IO MO: 6-9, 16 and 12). In some embodiments of the invention, the antibody is piMom19. In some embodiments of the invention, the immunoconjugate contains maytansinoid. In some embodiments of the invention, maytansinoid is ЮМ4. In some embodiments of the invention, the immunoconjugate contains a linker that is sulfo-5ZROV. In some embodiments of the invention, the immunoconjugate is IMOM853 (piMom19-sulfo-5ROV-YUOMA). 0013) In some variants of the implementation of the invention, the binding agent anti-ROI K1 (for example, pyMom19-sulfo-5ROV-YUM4) is administered in a dose of from about 1 to about 7.0 mg/kg, while kilograms of body weight lead to I VU , GVUM, V5A, or AIVUM (ABU). In some embodiments of the invention, the binding agent anti-ROI KI (for example, pyMom19-sulfo-5ROV-YUOMA) is administered in a dose of about 1.0 mg/kg, while kilograms of body weight lead to IVMU, I VMU, VBA, or AIVMU (ABU). In some embodiments of the invention, the binding agent anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-YUOMA) is administered in a dose of about 1.1 mg/kg, while kilograms of body weight lead to IVUM, I VMUU, VZA, or AIVMU (ABU). In some variants of the implementation of the invention, the binding agent anti-ROI K1 (for example, pyMom19-sulfo-5ROV-OMU) is administered in a dose of about 1.5 mg/kg, while kilograms of body weight lead to IVUM, I. VU, B5A, or AIVUM (ABU). In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-OMUYA) are administered in a dose of about 1.8 mg/kg, while kilograms of body weight lead to IVMU,

IIVMU, VBA, or AIVMU (OR). In some embodiments of the invention, the binding agent anti-

EO KI (for example, pyMom19-sulfo-5ROV-YUOMA4) is administered in a dose of about 2.0 mg/kg, while kilograms of body weight lead to IVUM, II VUU, B5BA, or AIVUM (AB). In some embodiments of the invention, the binding agent anti-ROI KI (for example, pyMom19-sulfo-5ROV-YUOMA) is administered at a dose of about 2.5 mg/kg, while kilograms of body weight lead to IVMU, I VMU, VBA, or AIVMU (ABU). In some embodiments of the invention, the binding agent anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-UOMA) is administered in a dose of about 2.8 mg/kg, while kilograms of body weight lead to IVUM, I VMUU, VZA, or AIVMU (ABU). In some variants of implementation of the invention

A binding agent anti-ROI K1 (for example, pyMom19-sulfo-5ROV-OMU) is administered in a dose of about 3.0 mg/kg, while kilograms of body weight lead to IVMU, I. VUM, VZA, or AIVMU (ABU ). In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-OMUYA) are administered in a dose of about 3.3 mg/kg, while kilograms of body weight lead to IVMU,

IIVMU, VBA, or AIVMU (OR). In some embodiments of the invention, the binding agent anti-

EOY CIs (for example, pyMom19-sulfo-5ROV-OMU) are administered in a dose of about 3.75 mg/kg, while kilograms of body weight lead to IVMUU, GVUM, VZA, or AIVMU (ABU). In some variants of the implementation of the invention, the binding agent anti-ROI KI (for example, pyMom19-sulfo-5ROV-YUOMA) is administered in a dose of about 4.0 mg/kg, while kilograms of body weight lead to IVMU, I VMU, VBA, or AIVMU (ABU). In some embodiments of the invention, the binding agent anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-YUOMA) is administered in a dose of about 4.1 mg/kg, while kilograms of body weight lead to IVUM, I VMUU, VZA, or AIVMU (ABU). In some embodiments of the invention, the binding agent anti-ROI K1 (for example, pyMom19-sulfo-5ROV-OMU) is administered at a dose of about 4.2 mg/kg, while kilograms of body weight lead to IVUM, I VUM, VZA or AIVUM (ABU). In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-OMA) are administered in a dose of about 5.0 mg/kg, while kilograms of body weight lead to IVMU,

IIVMU, VZA or AIVMU (AB). In some embodiments of the invention, the binding agent anti-

EO KI (for example, pyMom19-sulfo-5ROV-YUOMA4) is administered in a dose of about 5.5 mg/kg, while kilograms of body weight lead to IVUM, I! VUU, V5BA, or AIVUM (AB). In some embodiments of the invention, the binding agent anti-ROI KI (for example, pyMom19-sulfo-5ROV-YUOMA) is administered at a dose of about 5.6 mg/kg, while kilograms of body weight lead to IVMU, I VUM, VBA or AIVMU (ABU). In some embodiments of the invention, the binding agent anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-YUOMA) is administered at a dose of about 6.0 mg/kg, while kilograms of body weight lead to IVUM, I VMU, VZA or AIVUM (ABU). In some embodiments of the invention, the binding agent anti-ROI K1 (for example, pyMom19-sulfo-5ROV-OMU) is administered at a dose of about 6.5 mg/kg, while kilograms of body weight lead to IVUM, I VUM, VZA or AIVUM (ABU). In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-OMUYA) are administered in a dose of about 7.0 mg/kg, while kilograms of body weight lead to IVMU,

IIVMU, VBA or AIVMU (OR). In some variants of implementation of the invention, kilograms of body weight lead to AIVUM (ABU). bo 00141 In accordance with the methods described herein, the binding agent anti-

EOG KI (for example, pPiMom19-sulfo-5ZROV-YuOM4) can be administered once every 4 weeks. In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-OMU) are administered once a week. In some variants of the implementation of the invention, the binding agent anti-ROI K1 (for example, piMom19-sulfo-5ROV-OM4) is administered once every 2 weeks. In some embodiments of the invention, the binding agent anti-ROIK1 (for example, piMom19-sulfo-

ZROV-YUOMU) are administered about once a week. 0015) In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1 to about 7 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1.5 mg/kg to about 6.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1.5, 2.0, 2.5, 3, 3.75, 4.0, 4.1, 4.2, 5.0, 5.5 and 6.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate is administered at a dose of about 1.1, 1.8, 2.5, 3.3 and 4.2 mg/kg/hour once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 1.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-Swarm K1 immunoconjugate is administered at a dose of about 1.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI K1 is administered at a dose of about 1.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI KI1 is administered at a dose of about 1.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI K1 is administered at a dose of about 2.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI K1 is administered at a dose of about 2.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI KI1 is administered at a dose of about 2.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 3.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 3.3 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 3.75 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 4.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the anti-ROI NO immunoconjugate is administered at a dose of about 4.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-EOI K1 is administered at a dose of about 4.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 5.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 5.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 5.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 6.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 is administered at a dose of about 7.0 mg/kg once a week for three weeks in accordance with a four-week regimen. 0016) In some embodiments of the invention, an immunoconjugate (for example, piMom19-sulfo-

ZROV-YUOMA) are administered in a dose of about 1 to 7 mg/kg, while kilograms are brought to IVMU,

And VMU, VZA or AIVUM (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks in accordance with the four-week regimen. In some embodiments of the invention, the immunoconjugate (for example, pyMom19-sulfo-5ROV-OMU) is administered at a dose of about 1.5 mg/kg to about 6 mg/kg, while the kilograms lead to IVUM, I VUU, VBA or AIVMU (AbBU)), and at 60, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-EOI B1 (for example, piMom19-sulfo-5ROV-UOMA) is administered in a dose of about 1 mg/kg, while kilograms are brought to IVMU, GVUM, VA or AIVUM (AB)U)) , and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI KI! (for example, PpyMom19-sulfo-5ROV-OMAU) is administered in a dose of about 1.1 mg/kg, while the kilograms lead to IVMU, I VUM, VBA or AIVUU (AbBu)), and at the same time the immunoconjugate is administered once per a week for three weeks in accordance with the four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, pyMom19-sulfo-5ZROV-YUOM4) is administered in a dose of about 1.5 mg/kg, while kilograms are brought to IVUMU, I VUMU, VZA or AIVMU (ABU) ), and at the same time, the immunoconjugate is administered once a week for three weeks according to the four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 (for example, piMom19-sulfo-

ZROV-OMUYA) is administered at a dose of about 1.8 mg/kg, while kilograms are brought to IVUM, I VUM, VBA or AIVUM (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen . In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, piMom19-sulfo-5ROV-UOMAU) is administered at a dose of about 2 mg/kg, while the kilograms lead to IVUU, IVUM, B5A or AIVUM (AB), and at this immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-YUOMA) is administered in a dose of about 2.5 mg/kg, while kilograms are brought to IVMU, GVUM, VA or AIVUM (AB)U )), and at the same time, the immunoconjugate is administered once a week for three weeks according to the four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI KI! (for example, PpyMom19-sulfo-5ROV-OMAU) is administered at a dose of about 2.8 mg/kg, while kilograms are brought to IVMU, I VUM, VBA or AIVUU (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks in accordance with the four-week regime. In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, pymMom19-sulfo-5ROV-YUMAU) is administered in a dose of about 3 mg/kg, while kilograms lead to IVUM, I VUU, B5A or AIVUM (ABU)). and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some

Among the variants of implementation of the invention, the immunoconjugate anti-ROI K1 (for example, piMom19-sulfo-5ROV-

OMA) are administered in a dose of about 3.3 mg/kg, while kilograms are brought to IVMU, VU, VZA or

AIVMU (ABU)), and at the same time, the immunoconjugate is administered once a week for three weeks in accordance with the four-week regimen. In some embodiments of the invention, the anti-ROI K1 immunoconjugate (for example, pyMom19-sulfo-5ROV-YUMA4) is administered at a dose of about 3.75 mg/kg, while the kilograms are brought to IVUMU, IVUMU, VZA or AIVMU (ABU)) , and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 (for example, piMom19-sulfo-

ZROV-YUOMUA) is administered at a dose of about 4 mg/kg, while kilograms are brought to IVUM, I VUM, VBA or AIVUM (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, pPiMom19-sulfo-5ROV-YUMU) is administered in a dose of about 4.1 mg/kg, while kilograms lead to IVMUU, I VUM, B5A or AIVUM (AB) , and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-UOMA) is administered at a dose of about 4.2 mg/kg, while kilograms are brought to IVMU, GVUM, VA or AIVUM (AB)U )), and at the same time, the immunoconjugate is administered once a week for three weeks according to the four-week regimen. In some variants of implementation of the invention, the immunoconjugate anti-ROI KI! (for example, PpyMom19-sulfo-5ROV-OMAU) is administered at a dose of about 5 mg/kg, while the kilograms lead to IVUM, GVUM, VZA or AIVUU (ABU), and at the same time the immunoconjugate is administered once a week for three weeks according to the four-week regime. In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, pyMom19-sulfo-5ZROV-ЮОМ4) is administered at a dose of about 5.5 mg/kg, while the kilograms lead to IVUM, IVMUU, VBA or AIVMU (AbBU)) , and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some embodiments of the invention, the immunoconjugate anti-ROI K1 (for example, piMom19-sulfo-

ZROV-OMAYA) is administered at a dose of about 5.6 mg/kg, while kilograms are brought to IVMU, I VUM, VBA or AIVUM (ABU), and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen . In some variants of the implementation of the invention, the immunoconjugate anti-ROI K1 (for example, pyMom19-sulfo-5ROV-YUOMA) is administered at a dose of about 6 mg/kg, while kilograms are brought to IVUM, I VMU, VBA or AIVUM (AbBU)) , and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-EOI B1 (for example, pPiMom19-sulfo-5ROV-UOMA) is administered at a dose of about 6.5 mg/kg, while kilograms are brought to IVMU, GVUM, VA or AIVUM (AB)U )), and at the same time, the immunoconjugate is administered once a week for three weeks according to the four-week regimen. In some variants of the implementation of the invention, the immunoconjugate anti-ROI 1 (for example, PpyMom19-sulfo-5ROV-OMAU) is administered in a dose of about 7 mg/kg, while the kilograms lead to IVUM, GVUM, VZA or AIVUU (AbB.)). and at the same time, the immunoconjugate is administered once a week for three weeks according to a four-week regimen. In some variants of the implementation of the invention, kilograms lead to AIVMM (АВ.

I0017)| In some variants of implementation of the invention, binding agents anti-ROI K1 were introduced to obtain AS obtained in examples 1-6, and presented in figures 1-2 and 7-12. 0018) In some variants of the implementation of the invention, binding agents anti-ROI K1 were introduced to obtain Stach obtained in examples 1-6 and shown in figures 1-6 and 9-12.

I0019| In some embodiments of the invention, the binding agent anti-ROI K1 (for example, piMom19-sulfo-5ROV-OMA) is administered intravenously.

I0020| The methods described herein can be used to treat cancer. In some embodiments of the invention, the cancer is selected from the group consisting of cancer of the ovary, brain, breast, uterus, endometrium, pancreas, kidney (eg, renal cell carcinoma), and lung (eg, non-small cell lung cancer or bronchioloalveolar carcinoma (BSC) )). In some embodiments of the invention, the cancer is ovarian cancer or lung cancer. In some embodiments of the invention, the cancer is epithelial ovarian cancer. 0021) In some embodiments of the invention, the cancer expresses the polypeptide or nucleic acid of ROI K1. In some variants of the implementation of the invention, cancer is characterized by an increased level of expression of the BOYKI polypeptide, according to data measured by the immunohistochemical method (INS).

For example, in some variants of the implementation of the invention, the cancer is a cancer that expresses the ROY K1 polypeptide at the level of 1 hetero or higher according to ANN data. In some embodiments of the invention, the cancer is a cancer that expresses the ROI KI polypeptide at a level of 1 homo or higher than

According to INS data. In some embodiments of the invention, the cancer is a cancer that expresses the ROY KI1 polypeptide at the level of 2 hetero or higher according to ANN data. In some variants of the implementation of the invention, the cancer is a cancer that expresses the ROY KI polypeptide at the level of 2 homo or higher according to ANN data. In some variants of the implementation of the invention, the cancer is a cancer that expresses the ROY K1 polypeptide at the level of C hetero or higher according to the INS. In some variants of the implementation of the invention, the cancer is a cancer expressing the ROY K1 polypeptide at the level of C homo or higher according to the ANN. In some variants of the implementation of the invention, the cancer is a lung cancer that expresses the ROY KI1 polypeptide at the level of 2 hetero or higher according to ANN data. In some variants of the implementation of the invention, the cancer is a lung cancer that expresses the ROY KI1 polypeptide at the level of C hetero or higher according to ANN data. In some embodiments of the invention, the cancer is an epithelial ovarian cancer (eg, platinum-resistant or recurrent or refractory) that expresses the ROY KI polypeptide at level 2 hetero or higher. In some embodiments of the invention, the cancer is an epithelial ovarian cancer (eg, platinum-resistant or recurrent or refractory) that expresses the ROY KI polypeptide at the C hetero level or higher.

In some variants of the implementation of the invention, the cancer is an endometrial cancer that expresses the BOY KI polypeptide at the level of 1 hetero or higher according to ANN data. in some variants of the implementation of the invention, the cancer is an endometrial cancer that expresses the ROY K1 polypeptide at the level of 2 hetero or higher according to the data.

I0022| In some embodiments of the invention, the methods additionally include administering a steroid to the patient. The steroid can be administered in the form of premedication, that is, before the administration of the binding agent anti-ROI K1. The steroid may be dexamethasone.

I0023| The methods described in this document can lead to a reduction in the size of the tumor. The methods described in this document can lead to a decrease in CA125 levels in patients with ovarian cancer. In one example, CA125 levels are measured in a sample obtained from an ovarian cancer patient before treatment and then one or more times after treatment, with a decrease in CA125 levels over time indicating therapeutic efficacy. The methods described herein may result in an increase in the time interval between cancer treatment sessions.

The methods described in this document may lead to an increase in the duration of the progression-free period (PE5). The methods described in this document can lead to an increase in the period of remission (OE5). The methods described in this document can lead to an increase in overall life expectancy (05). The methods described in this document may lead to an increase in complete response (CR) rates. The methods described in this document may lead to an increase in the rate of partial response (PE). The methods described herein can lead to stable disease (50). The methods described in this document can lead to a more pronounced reduction in the rate of disease progression (RO).

The methods described herein may result in a reduction in time to disease progression (TPR).

I0024| In particular, the application regimens presented herein provide an optimal balance between efficacy (eg, LC) and reduced toxicity, as demonstrated, for example, in Examples 1-4 and Figures 1-7.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS/FIGURES

I0025| Figures TA and B present the pharmacokinetic data obtained from administration of IMOM853 (from 0.15 mg/kg to 7.0 mg/kg) as described in Example 1. Figure 1B presents the summary pharmacokinetic data, which includes the data from 1A and additional data obtained from additional patients. (0026) Figures 2A-B show reactions and occurrence of ophthalmic toxicity in patients with different values of Stach and AOSo-g4a and AOSo-vvv.

I0027| Figure C shows the range of Stach values measured at different doses. 00281 Figure 4 shows the dependence of Stakh on the patient's body weight.

I0029| Figure 5 shows the variance in Stach and AOSo-ha associated with alternative dosing approaches.

Figure 6 shows the predicted dependence of Stakh on body weight using alternative dosing approaches. 0031) Figure 7 shows a graph of the values of AOSo-g4 observed in 24 patients receiving 3.3, 5 or 7 mg/kg IMOM853 based on total body weight (actual). These values were compared with the predicted values if all patients were treated with 5 mg/kg of total body weight (TVUU 5 mg/kg) and the predicted values if all patients received doses of 5, 5.4, or 6 mg/kg based on the adjusted value of the ideal body weight (ABU 5, 5,4 or 6). Actual data on 7 patients treated at doses of 5 mg/kg adjusted ideal body weight (actually 5 ABU)) are also shown. The percentage of patients who have

Zo or will have predicted AOC values above the ophthalmic toxicity threshold, shown in the table below the graph. 0032 Figure 8 shows the values of AOso-2a for all patients in the range of 3.3-7.0 mg/kg.

The TVUM group was used to calculate the predicted values of Aso-ha4 in the indicated doses.

The actual AOSo-g4a data of the patients for the indicated doses are also displayed, including the data of the group of patients dosed at 5.0 and 6.0 adjusted ideal body weight (AIBM/). 0033) Figure 9 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMOM853 in mice treated with single doses of 2.8 mg/kg, 5.6 mg/kg, or 8.5 mg/kg immunoconjugate .

I0034| Figure 10 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMOM853 in mice treated with single doses of 8.5 mg/kg, three daily doses of 2.8 mg/kg, or three doses of 2.8 mg/kg every three days.

I0035)| Figure 11 shows the antitumor activity, predicted plasma concentration, and other pharmacokinetic parameters of IMOM853 in mice treated with single doses of 5.6 mg/kg or 1.4 mg/kg daily for three days. 0036) Figure 12 shows the antitumor activity, predicted plasma concentration and other pharmacokinetic parameters of IMOM853 in mice treated with single doses of 8.5 mg/kg or 2.8 mg/kg every week for three weeks.

DETAILED DESCRIPTION OF THE ESSENCE OF THE INVENTION

І0037| The present invention provides new administration schemes for immunoconjugates that bind to BOY K1.

I. Terms (0038) To facilitate understanding of the present invention, a number of terms and expressions are defined below.

I0039| The terms "human folate receptor 1", "ROI K1" or "folate receptor alpha (EV-o)", as used herein, refer to any native human ROI CT, unless otherwise indicated. Thus, all of these terms can refer to a protein or nucleic acid sequence as defined herein. The term "K1 Swarm" includes "full-size" unprocessed K1 Swarm, as well as any form of CI Swarm resulting from processing within the cell. In addition, the term includes naturally occurring variants of BOI K1, such as splice variants, allelic variants, and isoforms. The BOY K1 polypeptides described herein can be isolated from numerous sources, such as various types of human tissues or other sources, or obtained by recombinant or synthetic methods. Examples of BOI K1 sequences include, but are not limited to, MSVI with inventory numbers P115328,

MP 001092242.1, AAX29268.1, AAX37119.1, MP 0579371 and MP 0579361. 00401) The term "antibody" means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid or combinations of the above, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" includes intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Ear, Rab, E(abB)2 and Em fragments), single chain mutants of Em (5cEm), polyspecific antibodies such as bispecific antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, chimeric proteins containing an antigen-recognizing portion of an antibody, and any other modified immunoglobulin molecule containing an antigen-recognition site, to as long as the antibodies demonstrate the desired biological activity. The antibody can belong to any of the five main classes of immunoglobulins: IdA, dO, IdCHE, Ids, and dm, or their subclasses (isotypes) (for example, Ids1, Ids2, Id, Ids4, IdDA1, and IdAg), based on the identity of their heavy chain constant domains, designated alpha, delta, epsilon, gamma, and mu, respectively. Different classes of immunoglobulins contain different and well-known subunit structures and three-dimensional configurations.

Antibodies can be unconjugated or conjugated to other molecules, such as toxins, radioisotopes, etc.

I0041| A "blocking" antibody or "antagonist" antibody is one that inhibits or reduces the biological activity of the antigen to which it binds, such as Swarm CAT. In some embodiments of the invention, blocking antibodies or antagonist antibodies significantly or completely inhibit the biological activity of the antigen. Biological activity can be reduced by 10 95, 20 95, 30 95, 50 95, 70 95, 80 95, 90 95, 95 95 or even 100 95.

I0042| The term "anti-BOI K1 antibody" or "antibody that binds to BOI CT" means an antibody that is capable of binding to EROI CI with sufficient affinity such that the antibody is suitable as a diagnostic and/or therapeutic agent for targeting K1 FIGHTS. The degree of binding of anti-ROI KI antibodies! with a foreign, non-BOI KI protein can be less than

About 10 95 from the binding of antibodies to ROI K1 according to data, for example, radioimmunoassay (KIA).

In some embodiments of the invention, the dissociation constant (Ka) of the antibody that binds to

EOGE, is x 1 μM, x 100 nm, x 10 nm, x 1 nM or x 0.1 nM.

II0043| The term "antibody fragment" refers to a portion of an intact antibody and refers to the antigen-recognizing variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Rab, Rab, P(ab)2, and Em fragments, linear antibodies, single-chain antibodies, and polyspecific antibodies formed from antibody fragments. (0044| "Monoclonal antibody" means a homogeneous population of antibodies involved in highly specific recognition and binding of a single antigenic determinant or epitope.

In contrast, polyclonal antibodies usually include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" includes both intact and full-length monoclonal antibodies, as well as antibody fragments (such as Bar, Rar, E(ab)2,

Em), single-chain (5Cem) mutants, chimeric proteins containing part of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site. In addition, "monoclonal antibody" means such antibodies obtained by any number of methods, including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals. (0045) The term "humanized antibody" refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. As a rule, humanized antibodies are human immunoglobulins, in which residues of the complementarity determination site (CSP) are replaced by CSP residues of non-human species (for example, mouse, rat, rabbit, hamster) that have the desired specificity, affinity and valence (Copez et al. !., 1986, Maishge, 321:522-525; Niesptapp ei a!., 1988, Maishge, 332:323-327; Metoeuep ei aI., 1988, bsivepse, 239:1534-1536). In some cases, the residues of the Em framework region (EC) of the human immunoglobulin are replaced by the corresponding residues of the antibody of a non-human species that have the desired specificity, affinity and valence. In addition, the humanized antibody can be modified by replacing additional residues in the Em framework and/or within the modified non-human residues, in order to refine and optimize the specificity, affinity and/or valence of the antibody. In general, a humanized antibody contains substantially all of the 60 at least one, and usually two or three, variable domains that contain all or substantially all of the SOC regions that correspond to a non-human immunoglobulin, while all or substantially all of the EC regions are derived from the consensus sequence of human immunoglobulin.

Additionally, the humanized antibody may contain at least a portion of an immunoglobulin constant region or domain (Bs), usually from a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in US Patent 5,225,539. In some embodiments of the invention, a "humanized antibody" is an antibody with a modified surface.

I0046| "Variable region" of an antibody means the variable region of the light chain of the antibody or the variable region of the heavy chain of the antibody, alone or in combination. Each heavy and light chain variable region consists of four framework regions (FCs) connected by three complementarity-determining regions (CRIs), also known as hypervariable regions. COMs in each chain are held together in close proximity to the EC and, together with COMs from another chain, participate in the formation of the antigen-binding site of antibodies. There are at least two methods for determining SOC: (1) an approach based on interspecies variability of sequences (ie, Kabai ei aI. Zedcepsez oi Rgoieip5 oi Ittipoiodisa! Ipiegevi, (Biy ed., 1991, Maiopai Ipziishev oi Neapyi, VeshShezaa MAa.)) ; and (2) an approach based on crystallographic studies of antigen-antibody complexes (AI-Iagikapi et al. (1997) U. Moyes. Viol. 273:927-948)). Additionally, combinations of these two approaches are sometimes used in the art to determine SOC.

II0047| The Karai numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g. Kabai ei ai,, zediepse5 oi Ittypoiodisa! Ipiege5i. 5Ip Ei. Rybiis Neain zZegmise , Maiopai Ipziyshez oi Neany, Veipezaa, Ma. (1991)). (0048) Amino acid position numbering according to Cabrai means the numbering system used for heavy chain variable domains or light chain variable domains in the compilation of antibodies in Cabrai, Zedioepsez, Rgoyeip5, Ittypo!odisai Iptegevi, 5Ip

EY Ribiis Neatsi zZegmise, Maiopai Ipziyshez oi Neakn, Veipezaa, Ma. (1991). Using this numbering system, the actual linear sequence of amino acids may contain fewer or more amino acids corresponding to a truncation or insertion in the EC or SOC of the variable domain.

For example, the heavy chain variable domain may contain a single amino acid insertion (residue 52a according to Cabrai) after residue 52 of H2 and inserted residues (eg, residues 82a, 8260 and 82c, etc. according to Cabrai) after residue 82 EC of the heavy chain.

Residue numbering according to Karai can be determined for a particular antibody by aligning the homology region of the antibody sequence with a "standard" Karai numbered sequence. Instead, Spoiia refers to the arrangement of structural loops (Spoiia apa I e5K 9. Moi. Vio!. 196:901-917 (1987)). The end of the loop of Spoipia SOC-

NO, when numbering according to the Karai numbering convention, it varies from НЗ2 to НЗА4, depending on the length of the loop (this is due to the fact that the Kabay numbering scheme places inserts in НЗ5БА and НЗ5ОВ; if З5А and 358 are present, the loop ends at 32; if only Z5A is present, the loop ends at 33; if Z5A and 358 are present, the loop ends at 34). Hypervariable regions of AVM represent a compromise between CaBbA SOC and SpOipia structural loops, and are used by antibody modeling software

ARM from Ohio Moiesshiag.

: cafe NK Zh iy VEZH b : o VPbedya kaBy VM. Sa she sha and I iv in (Numbering according to KaBay and: Eh zhk SHE a YAKI ЖЖ, ZHE DE, ih Ok ! she nn che na : inNumevztsiai for SVO yi shi! chne ANA ON : «zrche zhi Zhe zhk Kf uyu : (0049) The term "human antibody" means an antibody produced by a human, or an antibody containing an amino acid sequence that corresponds to an antibody produced by a human, produced by any technique known in the art. the term human antibody includes intact or full-length antibodies, fragments thereof, and/or antibodies that contain at least one human heavy and/or light chain polypeptide, such as an antibody containing mouse light chain and human heavy chain polypeptides.

IOO50| The term "chimeric antibodies" refers to antibodies in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Of course, the variable region of both light and heavy chains corresponds to the variable region of antibodies obtained from the same mammalian species (for example, mouse, rat, rabbit, etc.) with the desired specificity, affinity, and valence, while the constant regions are homologous antibody sequences, obtained from another species (usually a human), to avoid an immune reaction in the specified species.

I0O51| The terms "epitope" or "antigenic determinant" are used interchangeably herein and refer to the portion of an antigen that a particular antibody can recognize and specifically bind to. If the antigen is a polypeptide, epitopes can be formed by both adjacent amino acids and non-adjacent amino acids brought together as a result of tertiary folding of the protein. Epitopes formed by contiguous amino acids are usually preserved upon protein denaturation, whereas epitopes formed by tertiary folding are usually lost upon protein denaturation. An epitope usually contains at least 3, and more often at least 5 or 8-10 amino acids in a unique spatial conformation.

І0052| "Binding affinity" generally refers to the strength of the sum of the non-covalent interactions between one binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:11 interaction between members of a binding pair (eg, antibody and antigen). The affinity of the molecule X relative to its partner Y, in general, can be represented by the dissociation constant (Ka). Affinity can be measured by general methods known in the art,

In particular, those described in this document. Antibodies with low affinity generally bind to the antigen slowly and tend to dissociate easily, while antibodies with high affinity generally bind to the antigen more quickly and tend to bind for a longer time. Numerous methods of measuring binding affinity are known in the art, and any of them can be used for the purposes of the present invention. Specific illustrative embodiments are described below. 0053) "Or better", as used herein with reference to binding affinity, means stronger binding between a molecule and its binding partner. "Or better" as used herein means stronger binding represented by a lower numerical value of Ka. For example, in the case of an antibody with an antigen affinity of "0.6 nM or better," the antibody's antigen affinity is "0.6 nM, i.e., 0.59 nM, 0.58 nM, 0.57 nM etc., or any value less than 0.6 nM. 0054) "Specifically binds", in general, means that the antibody binds to the epitope by means of its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. In accordance with this term, an antibody is said to "specifically bind" to an epitope if it binds to such epitope with its antigen-binding domain more readily than it would bind to a random, unrelated epitope The term "specificity" is used herein to refer to the relative affinity with which a particular antibody binds to a particular epitope. For example, antibody A may be considered to have higher specificity for a given epitope than antibody B, or antibody A may be indicated to bind epitope C with greater specificity than with the cognate epitope "0".

I0055)| By "preferential binding" is meant that the antibody specifically binds to the epitope more readily than it would bind to a related, similar, homologous, or similar epitope. Thus, an antibody that "preferentially binds" to a given epitope is more likely to bind to that epitope than to a cognate epitope, even though such an antibody may cross-react with a cognate epitope. 0056) An antibody is meant to "competitively inhibit" the binding of a reference antibody to a given epitope if it preferentially binds to such epitope to such an extent that it blocks, to some extent, the binding of the reference antibody to the epitope.

Competitive inhibition can be determined by any method known in the art, for example, a competitive EHIBA assay. An antibody can be designated as competitively inhibiting binding of a reference antibody to a given epitope by at least 90 to, at least 80 to 95, at least 70 to 95, at least 60 to 95, or at least 50

What

ЙОО57| The phrase "substantially similar" or "substantially the same" as used herein means a sufficiently high degree of similarity between two numerical values (generally, one associated with an antibody of the invention, and

(otherwise related to the reference antibody/comparator) such that one of ordinary skill in the art would consider the difference between the two values to be small or of no biological and/or statistical significance in the context of the biological characteristic measured by said values (for example, Ka value). The difference between the two values may be less than about 50 95 , less than about 40 95 , less than about 30 95 , less than about 20 95 , or less than about 10 95 as a function of the value for the reference antibody/comparator. 0058) An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells or compositions include purified to such an extent that they no longer exist in the form in which they are found in nature. In some embodiments of the invention, the selected antibody, polynucleotide, vector, cell or composition is substantially pure. 0059) As used herein, "substantially pure" means material that is at least 50 95 pure (ie, free from contaminants), at least 90 95 pure, at least 95 95 pure, at least 98 95 pure, or at least 99 95 pure. 0060) The term "immunoconjugate" or "conjugate" as used herein refers to a compound or derivative thereof coupled to a cell-binding agent (ie, an anti-

EOIKI or its fragment) and is determined by the general formula: C-I-A, where C is a cytotoxin, Y is a linker, and A is an anti-ROI KI antibody! or antibody fragment. In addition, immunoconjugates can be determined by the general formula in the reverse order: A-I1 -0.

I0061) The term "IMOM853" means the immunoconjugate described in this document containing the antibody piMom19, a linker, sulfo5ROV and maytansinoid OM4. The piMom19 antibody contains a variable heavy chain with the amino acid sequence ZEO IU Mo: C and a variable light chain with the amino acid sequence ZEO IU Mo: 5. 00621) "Linker" is any chemical fragment capable of binding a compound, a common drug , such as maytansinoid, with a cell-binding agent, such as an anti-ROI K1 antibody or fragment thereof, in a stable, covalent form. Linkers may be sensitive or may be substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage, under conditions in which the compound or antibody remains active. Suitable linkers are well known in the art and include, for example, disulfide groups, thioester groups, acid-labile groups, photolabile groups, peptidase-labile groups and esterase-labile groups. In addition, linkers include charged linkers and hydrophilic forms thereof, as described herein and known in the art. 0063) The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals in which a population of cells is characterized by disordered cell growth. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.

More specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver, bladder cancer, hepatoma, breast cancer, colon cancer, colon and rectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma and a variety of head and neck cancers. The cancer may be a cancer that expresses BOI KI1. (0064) "Tumor" and "neoplasm" refer to any mass of tissue resulting from excessive growth or proliferation of cells, whether benign (noncancerous) or malignant (cancerous), including precancerous lesions.

I0O65| The terms "cancer cell" "tumor cell" and their grammatical equivalents refer to the general population of cells derived from a tumor or precancerous lesion, including both non-tumorigenic cells that make up the bulk of the tumor cell population and tumorigenic stem cells (cancer stem cells). As used herein, the term "tumor cell" will be modified by the term "non-tumorigenic" to refer exclusively to those tumor cells that lack the ability to renew and differentiate to distinguish such tumor cells from cancer stem cells.

I006b| The term "subject" means any animal (eg, mammal), including, but not limited to, humans, non-human primates, rodents, etc., which is intended to be

With the recipient of a specific treatment regimen. Of course, the terms "subject" and "patient" are used interchangeably herein to refer to a human subject.

I0067| The term "ideal body weight" (IBMU) means the value of the indicator, which is not directly related to the total body weight. IVUU is an estimate of mass with correction for height, sex, and additionally for physique. IVUM can be calculated, for example, by the formulas IVUM - 0.9Н- 88 (for men) and IVUM - 0.9Н - 92 (for women), where Н - height in cm. (0068) The term "dry body weight" ( And BMI) means the value of the indicator, which takes into account the relative fat mass of the body (95 BMI). GVUM is equal to the total body weight minus the product of BMI and mass.

IVUM can be calculated, for example, by formulas I VUM - 1.10 x mass in kg - 128 Fmass in kg| 2? / 1100 x height in meters)| 2) (for men) and I VUM - 1.07 x mass in kg - 148 (mass in kg12? / (100 x height in meters | 2) (for women).

I0069| The term "adjusted ideal body weight" (AIVMU) or "adjusted ideal weight" (AWU)) means the value of the indicator, which takes into account gender, total body weight and height. AIVUM and

OR are used interchangeably. AIVMU (AB) can be calculated, for example, by the formula ABU - IVMU - 0.4 (mass in kg - IVMU). 0070 IVUU, I VUM and AIVMU (ABU) are discussed in more detail in Sgeep and Yuiyi, Vgyi5p

Wow! oi Siipisai Raptasoiodu 58: 119-133 (2004), which is incorporated herein by reference in its entirety.

ИЙ0О071| Administration "in a combination of 3" with one or more additional therapeutic agents includes simultaneous (competitive) and sequential administration in any order. (0072) The term "pharmaceutical preparation" means a preparation that is in a form that enables the manifestation of the biological activity of the active ingredient in an effective way, and does not contain additional components that would be unacceptably toxic to the subject to whom the preparation is administered. The drug can be sterile.

I0073| An "effective amount" of an antibody or immunoconjugate, as disclosed herein, is an amount sufficient to achieve a specifically stated purpose. "Effective amount" can be determined in an empirical and formulaic manner, relative to the stated purpose.

I0074| The term "therapeutically effective amount" means an amount of an antibody or other drug effective in terms of "treating" a disease or disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the size of the tumor; suppress (that is, slow down to some extent, and in a certain version of the invention, stop) the infiltration of cancer cells to peripheral organs; suppress (that is, slow down to some extent, and in a certain variant of the implementation of the invention stop) metastasis of the tumor; suppress, to some extent, tumor growth; relieve, to some extent, one or more symptoms associated with cancer; and/or result in a favorable response, such as an increase in progression-free (PE) duration, remission (OE5) or overall survival (05), complete response (CR), partial response (PE) rates, or, in some cases , stable disease (50), reduction in rate of disease progression (RO), reduction in time to disease progression (TPR), reduction in CA125 in ovarian cancer, or any combination thereof. 0075) See definition of “treatment” in this document. To the extent that a drug can prevent tumor growth or cause the death of existing cancer cells, it can be cytostatic and/or cytotoxic. In some variants of the implementation of the invention, the identification of increased levels of ROIK! allows the administration of reduced amounts of BOI K1-targeted therapeutic agent to achieve the same therapeutic effect seen at higher doses. "Prophylactically effective amount" means an effective amount, at such doses and for such necessary time periods, to achieve the desired prophylactic result. Of course, but not necessarily, because the prophylactic dose is used in subjects before the onset or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

I0076)| The term "respond favorably" generally means the induction of a favorable state in the subject. In relation to the treatment of cancer, the term means providing a therapeutic effect in a subject.

A positive therapeutic effect in cancer can be measured in numerous ways (see

MA. Mebreg, U. Mysi. May 50:15-105 (2009)). For example, tumor growth inhibition, molecular marker expression, serum marker expression, and molecular imaging technologies can all be used to assess the therapeutic efficacy of an anticancer therapeutic agent. Regarding the inhibition of tumor growth, in accordance with the standards of the International Medical Association, T/s « 42 95 represents the minimum level of antitumor activity. T/C « 10 95 is considered as a high level of antitumor activity, where T/C (95) is the median volume of the treated tumor /

Median control tumor volume x 100. A favorable response can be assessed by

For example, by increasing the duration of the progression-free period (PE5), the period of remission (OE5) or overall life expectancy (05), the frequency of complete response (CR), partial response (PE), or, in some cases, stable disease (50) , a decrease in the rate of disease progression (RO), a decrease in the time to progression of the disease (TTR), a decrease in the level

CA125 in the case of ovarian cancer, or any combination thereof.

I0077| PE5, OEZ and O5 can be measured in accordance with established standards

by the National Cancer Institute and the US Food and Drug Administration for approval of new drugs. See doppzop ei ai, (2003) 9.

Siip. Opsoi 21(7):1404-1411.

І0078| "Progression Free Period" (PROP) means the period of time from registration to disease progression or death. PE5, in general, is measured using the method

Kariap-Miiieg and response evaluation criteria in standards for solid tumors (VESIBT) 1.1.

In general, progression-free refers to a situation in which the patient remains alive without the cancer getting worse.

І0079| "Progression Free Period" (PROP) means the period of time from registration to disease progression or death. PE5, in general, is measured using the method

Cariap-Miegue and response assessment criteria in the standards for solid tumors (VECI5T) 1.1.

In general, progression-free refers to a situation in which the patient remains alive without the cancer getting worse.

I0080| "Complete response" or "complete remission" or "SC" indicates the disappearance of all signs of the tumor or cancer in response to treatment. This does not always mean that the cancer is cured.

I0081| "Partial response" or "RC" means a reduction in the size or volume of one or more tumors or lesions, or the spread of cancer in the body, in response to treatment.

I00821| "Stable disease" means disease without progression or recurrence.

In stable disease, there is neither enough tumor shrinkage to qualify as a partial response, nor enough tumor growth to qualify as progressive disease. 0083) "Progressive disease" means the appearance of new lesions or tumors and/or unequivocal progression of existing non-target lesions. Also, progressive disease can mean the tumor has grown by more than 20 percent since the start of treatment, as a result of increased mass or spread of the tumor. (0084) "Period of remission" (OE5) means the period of time during and after treatment during which the patient is disease-free. (0085) "Total life expectancy" (05) means the time from patient registration to death or the date the patient was last seen alive. O5 includes prolongation of life expectancy compared to naïve or treatment-naïve individuals or patients.

Overall life expectancy means a situation in which the patient remains alive for a certain period of time, such as one year, five years, etc., for example, from the time of diagnosis or treatment. 0086) "Decreasing CA125 levels" can be assessed according to the guidelines of the International Intergroup on Gynecological Cancer (GI). For example, SAT25 levels can be measured before treatment to establish a baseline SAT125 level. CA1T25 levels may be measured one or more times during or after treatment, and a decrease in CA125 levels over time compared to baseline is considered a decrease in CA125 levels. 00871 Terms such as "therapy" or "treatment" or "treat" or "alleviation" or "alleviation" refer to therapeutic measures that cure, slow, reduce the symptoms and/or stop the progress of a diagnosed pathological condition or disorder. Thus, those in need of treatment include those already diagnosed with or suspected of having a disorder. In some embodiments, a subject is successfully "treated" for cancer according to the methods of the present invention if the patient exhibits one or more of the following: a reduction in the number or total absence of cancer cells; decrease in tumor size; suppression or lack of infiltration of cancer cells to peripheral organs, including, for example, the spread of cancer into soft tissue and bone; suppression or absence of tumor metastases; suppression or absence of tumor growth; relief of one or more symptoms associated with a specific type of cancer; reduction of morbidity and mortality; improving the quality of life; reduction of tumorigenicity, tumorigenicity frequency or tumorigenicity potential of a tumor; decrease in the number or occurrence of cancer stem cells in the tumor; differentiation of tumorigenic cells to a non-tumorigenic state; an increase in the duration of the period without progression (PE5), the period of remission

Zo (OE5) or overall life expectancy (05), frequency of complete response (CR), partial response (RC), stable disease (50), reduction in the rate of disease progression (RO), reduction in time to disease progression (TTR), reduction in the level CA125 in ovarian cancer, or any combination thereof. (0088| Prophylactic or preventive measures refer to therapeutic measures that prevent and/or slow the development of a target pathological condition or disorder. Thus, those in need of prophylactic or preventive measures include those who are predisposed to developing the disorder and those in whom the disorder should be prevented .

I0089| The terms "conduct premedication" and "premedication" refer to therapeutic measures performed before the administration of an anti-BOIK1 therapeutic agent. For example, as described in more detail herein, a prophylactic agent such as a steroid may be administered about one week, about five days, about three days, about two days, or about one day or 24 hours prior to the administration of the therapeutic anti - EOYI B1.

The prophylactic agent can also be administered before the administration of the anti-EOI B1 therapeutic agent on the same day as the anti-EOI B1 therapeutic agent. 0090 The term "maximum concentration (Cmax) refers to the maximum concentration of the drug in the blood, which is measured after taking a dose of the drug.

I0091| The term "area under the pharmacokinetic curve" (AUC) refers to the total amount of drug in the blood after taking a dose of the drug. AOS can be determined over a certain period of time. Thus, for example, AOSCOo-" refers to the total amount of drug in the bloodstream over an infinite period of time after taking a dose of the drug. In yet another example, AOsCo-24 refers to the total amount of drug in the bloodstream within 24 hours after taking a dose of the drug. In yet another example, АСО-vv refers to the total amount of drug in the bloodstream within 168 hours (or 1 week) after taking a dose of the drug. (00921 "Apparent volume of distribution in the stationary phase" (Mech) means the ratio of the total amount of drug substance in the body to the concentration of the drug in the plasma, or the "apparent" volume necessary to include the entire volume of the drug, if the drug is in the same concentration throughout the body , as in plasma.0093) A "chemotherapeutic agent" is a chemical compound suitable for the treatment of cancer, regardless of its mechanism of action. Chemotherapeutic agents include, for example, 60 CO20 antagonists such as Rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, fludarabine,

etoposide, methotrexate, lenalidomide, chlorambucil, bentamustine and/or modified versions of such chemotherapy agents.

I0094| The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to amino acid polymers of any length. The polymer can be linear or branched, it can contain modified amino acids, and it can be interrupted by residues of a non-amino acid nature. The terms also include naturally or artificially modified amino acid polymer; for example, by disulfide bond formation, glycosylation, lipidation, adethylation, phosphorylation, or any other manipulation or modification, such as conjugation to a label component. In addition, the definition includes, for example, polypeptides containing one or more analogs of amino acids (in particular, for example, unnatural amino acids, etc.), as well as other modifications known in this field of technology. It should be understood that since the polypeptides of this invention are based on antibodies, in some embodiments of the invention the polypeptides may exist as single chains or linked chains. (0095) The terms "identical" or percentage of "identity" in the context of two or more nucleic acids or polypeptides refer to two or more sequences or subsequences that are identical or that contain a specified percentage of nucleotides or amino acid residues that are identical when compared and alignments (with insertion of gaps if necessary) for maximum matching, disregarding any conservative amino acid substitutions as part of sequence identity. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art that can be used to achieve alignment of amino acid or nucleotide sequences. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Kahipei Ai., 1990,

Rgos. Mai)!. Asai. 5si., 87:2264-2268, modified in Kagtgiip eii ai., 1993, Rgos. Mai). Asai. 5si., 90:5873-5877, and built into the MVIGAZT and KhVI A5T programs (Aib5spii ei ai., 1991, Mysieis Asid5

Rev., 25:3389-3402). In some embodiments of the invention, Sarrea can be used

VI A5T, as described in Ai5sepa! ей а!., 1997, Mysivys Asiaz Nez. 25:3389-3402. VI A5T-2, MO-VI A5T-2

Koo) (AibBsPy! eyi ai.,, 1996, Meiyod5 ip Epgutoiodu, 266:460-480), APISM, APISM-2 (Sepepiesy,

South San Francisco, CA) or Medaidp (OMABTAC) is additional, publicly available software that can be used for sequence alignment. In some variants of the implementation of the invention, the percentage of identity between two nucleotide sequences is determined using the SAR program in the OSO software (for example, using the MUUzZdarapa.SMP matrix, a gap opening penalty of 40, 50, 60, 70 or 90 and a gap extension penalty of 1, 2, 3, 4, 5 or 6). In some alternative implementations of the invention, the SAR program in the CO program package, into which the Meeyetap and MUspbsp algorithm is built (9. Moi. Vioi. (48): 444-453 (1970)) can be used to determine the percentage of identity between two amino acid sequences (for example , using the Vio550it 62 matrix or the RAM250 matrix, a penalty for opening a gap 16, 14, 12, 10, 8, 6 or 4, and a penalty for extending a gap 1, 2, 3, 4, 5). Alternatively, in some embodiments of the invention, the percentage of identity between the sequences of nucleotides or amino acids is determined using the Mueg5 and MiSheg algorithm (SAVIO5, 4:11-17 (1989)).

For example, percent identity can be determined using AGISM (version 2.0), using RAM120 with a table of residues, a gap extension penalty of 12, and a gap opening penalty of 4. Suitable parameters for maximum alignment with a particular alignment software can be determined by one of skill in the art. this field of technology. In some embodiments of the invention, parameters used by default by the alignment software are used. In some embodiments of the invention, the percentage of identity "X" of the first sequence of amino acids to the second sequence of amino acids is calculated as 100 x (U/2), where M is the number of amino acid residues qualified as identical matches when aligning the first and second sequences (when aligning with visual inspection or a specific sequence alignment program), and 7 represents the total number of residues in the second sequence. If the length of the first sequence is greater than that of the second sequence, the percent identity of the first sequence to the second sequence will be longer than the percent identity of the second sequence to the first sequence.

I0096| As a non-limiting example, any particular polynucleotide having a certain percentage of sequence identity (eg, at least 80 95 identical, 60 at least 85 95 identical, at least 90 95 identical, and in some embodiments of the invention at least 95 95, 96 95 , 97 95, 98 95 or 99 95 is identical) to the reference sequence can, in some embodiments of the invention, be determined using the Fortune program (M/izsopbip zedcepse Apaiuziz RasKade, Version 8 for Opih, Sepeiyys5 Sotrshiyeg

Storr, Opimegeiu Kezeagsy Ragk, 575 Bsiepse Ogime, Madison, WI 53711). In Veznia, the local homology algorithm of Tii Umaieptap, Admapsez ip Ariyed MaShetaiysv 2: 482 489 (1981) is used to find the best segment of homology between two sequences. When using Wayne or any other sequence alignment program to determine whether a particular sequence is, for example, 95 95 identical to a reference sequence according to the present invention, the parameters are set such that the percent identity is calculated for the full-length reference nucleotide sequence, and that gaps in homology up to 5 95 of the total number of nucleotides in the reference sequence will be allowed.

I0097| In some embodiments of the invention, two nucleic acids or polypeptides of the invention are substantially identical if they contain at least 70,956, at least 75

Fo, at least 80 906, at least 85 95, at least 90 905, and in some embodiments of the invention at least 95 95, 96 95, 97 95, 98 95, 99 95 identical nucleotides or amino acid residues, when compared and aligned for maximum correspondence, according measurement data using sequence comparison algorithm or visual inspection.

The identity can be present over a stretch of sequences at least about 10, about 20, about 40-60 residues long, or any integer value in between, and can be present over a stretch longer than 60-80 residues, such as at least about 90-100 residues , and in some embodiments of the invention, the sequences are substantially identical along the entire length of the compared sequences, for example, such as the coding region of the nucleotide sequence. 0098) "Conservative amino acid substitution" is one in which a residue of one amino acid is replaced by a residue of another amino acid with a similar side chain. Families of amino acid residues with similar side chains are defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g.,

(Zo glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine , isoleucine) and aromatic side chains (for example, tyrosine, phenylalanine, tryptophan, histidine). For example, replacing phenylalanine with tyrosine is a conservative substitution. In some embodiments of the invention, conservative substitutions in the sequences of the polypeptides and antibodies according to the invention do not cancel the binding of the polypeptide or antibody containing the sequence of amino acids to the antigen(s), i.e., the BOI, to which the polypeptide or antibody binds. Methods for identifying conservative nucleotide and amino acid substitutions that do not abrogate antigen binding are well known in the art (see, e.g., Physiology, Biospet. 32: 1180-1 187 (1993); Corr. 12(10):879-884 (1999); and Vygkz ei ai. Rgos. Mai)!. Asad 5 BOTH 94:.412-417 (1997)). 0099) As used in this document and the claims, the words in the singular also mean the plural, unless the context clearly indicates otherwise. 00100) It should be understood that in all cases where embodiments of the invention are described in this document by means of the expression "comprising", other similar embodiments of the invention described in the terms "consisting of" and/or "which essentially consists of 3".

I00101| The term “and/or” as used herein in phrases such as “And and/or

B', includes 'A and B', 'A or B' and 'A' and 'B'. In addition, the term "and/or" as used in

BO such phrases as "A, B and/or C" include each of the following options: A, B and C; A, B or C; And or

C/AaboB; Vabo C; A ii S; A and B; B and C; (only) A; (only) B; and (only) S.

II. ROI B1-binding agents

І00102| In the methods described in this document, methods of introducing sequences that specifically bind to ROI KI ("ROI K1-binding agents") are proposed. In some embodiments of the invention, EOY K1-binding agents are antibodies, immunoconjugates, or polypeptides. The amino acid and nucleotide sequences of human ROY CT are known in the art, and are also given in this document as represented by 5EO IYUO Mo: 1 and 5EO IYU Mo: 2. Thus, in some variants of implementation of the invention, ROY K1-binding agents can connect to associate with the epitope 5EO IO Me: 1. because Y00103| Examples of therapeutically effective anti-ROI CT antibodies! can be found in

Publications of US application Mo. 2012/0009181, which is incorporated herein by reference.

An example of a therapeutically effective anti-ROI K1 antibody is piMom19 (M9346A). Polypeptides

ZEO IU Mo: 3-5 contain the variable domain of the heavy chain of piMom19 (MOU93464A) and the variable domain of the light chain version 1.00, the variable domain of the light chain version 1.60 of piMom19, respectively. In some embodiments of the invention, the piMom19 anti-ROIK1 antibody contains the variable domain of the heavy chain represented by 5EO IU MO: 3 and the variable domain of the light chain represented by BEO IU MO: 5 (version 1.60 with piMom19). In some embodiments of the invention, the PimMOom19 (M9346A) antibody is encoded by plasmids deposited on April 7, 2010 under the terms of the Budapest Treaty in the American Type Culture Collection (ATSC), located at 10801 University Boulevard, Manassas,

Virginia 20110, under ATCC inventory numbers PTA-10772 and PTA-10773 or 10774.

Examples of BOYKI immunoconjugates suitable for therapeutic methods according to the invention are given below.

I00104| In some embodiments of the invention, Swarm K1-binding agents are humanized antibodies or antigen-binding fragments thereof. In some embodiments of the invention, the humanized antibody or fragment is an antibody with a modified surface or its antigen-binding fragment. In other variants of implementation of the invention, the binding agent with ROI K1 is a fully human antibody or its antigen-binding fragment. 00105) In some variants of implementation of the invention, Swarm K1-binding agents cause one or more of the following effects: induce stable disease, inhibit the proliferation of tumor cells, reduce the tumorigenicity of the tumor, reduce the frequency of occurrence of cancer stem cells in the tumor, inhibit tumor growth, increase survival , initiate the death of tumor cells, differentiate tumorigenic cells to a non-tumorigenic state, or prevent tumor cell metastasis.

IІ00106| In some variants of implementing the invention, the BOY K1-binding agent is an antibody that has the property of causing antibody-dependent cellular cytotoxicity (AICT). 00107) In some variants of implementation of the invention, BOY K1-binding agents are capable of reducing tumor volume. The ability of ROI K1-binding agent to reduce the volume of the tumor can be estimated,

For example, by measuring the 95T/C value, which is the median tumor volume in treated subjects divided by the median tumor volume in control subjects. In some embodiments of the invention, immunoconjugates or other agents that specifically bind to

Human EOGKI1, initiate cell death with the help of a cytotoxic agent. For example, in some embodiments of the invention, an antibody to the human BOY KI antibody is conjugated with maytansinoid, which is activated in tumor cells that express the ROI K1 protein, by internalization. In some embodiments of the invention, ROI K1-binding agents are capable of inhibiting tumor growth. In some embodiments of the invention, BOY K1-binding agents are capable of inhibiting the growth of an immo tumor (for example, in a mouse xenograft model and/or in a person with cancer). 00108) ROI B1-binding molecules can be antibodies or antigen-binding fragments that specifically bind to BOI CIs containing SOC piMom19 (MU9346A), which contains up to four (ie, 0, 1, 2, C or 4) conservative amino acid substitutions for SOCs, e.g., where the antibodies or fragments do not contain the six COMs of murine Mom19 (ie, ZEO IU

Mo: 6-9, 16 and 12). The polypeptides may contain one of the individual variable light chains or variable heavy chains described herein. In addition, antibodies and polypeptides can contain both a variable light chain and a variable heavy chain. 00109) In some embodiments of the invention, the BOY K1-binding molecule is an antibody or an antigen-binding fragment containing the sequences 5EO IYU Mo: 6-10 and the sequence ZEO IYUO Mo: 12. In some embodiments of the invention BOY K1 - the binding molecule is an antibody or a binding fragment with an antigen containing sequences of FEO IU

Mo: 6-9 and sequences of BEO IU Mo: 11 and 12.

I00110| Additionally provided are polypeptides comprising a polypeptide having at least about 90 to 95 sequence identity with "EO IU Mo: 3, 5EO IU Mo: 4 or 5ZEO

IO Mo: 5. In some embodiments of the invention, the polypeptide includes a polypeptide having at least about 95 95, at least about 96 95, at least about 97 95, at least about 98 95, or at least about 99 95 sequence identity with ZEO

IO Me: 3, ZEO IO Mo: 4 or 5EO IU Mo: 5. Thus, in some embodiments of the invention, the polypeptide includes (a) a polypeptide having at least about 95 95 sequence identity with BZEO IUO Mo: 3, and/or (B) a polypeptide having at least about 95 95 60 sequence identity with zZEO IU Mo: 4 or 5EO IUO Mo: 5. In some embodiments of the invention, the polypeptide includes (a) a polypeptide containing the amino acid sequence 5EO IU Mo:

WITH; and/or (B) a polypeptide containing the amino acid sequence ZEO IU Mo: 4 or ZEO IO Mo: 5. In some embodiments of the invention, the polypeptide is an antibody and/or a polypeptide that specifically binds to BOI K1. In some embodiments of the invention, the polypeptide is a murine, chimeric, or humanized antibody that specifically binds to BOY K1. In some embodiments of the invention, the polypeptide having a certain percentage of sequence identity with "BO IUO Mo: 3, ZEO IUO Mo: 4 or 5EO IUO Mo: 5 differs from 5EO IUO Mo: C,

ZEO IU Mo: 4 or 5EO IU Mo: 5 only by conservative substitutions of amino acids. 00111) Polypeptides may contain one of the individual light chains or heavy chains described herein. Antibodies and polypeptides can contain both a light chain and a heavy chain. 00112) Monoclonal antibodies can be obtained using hybridoma methods, such as those described by Koijeg and Miibijeip (1975) Maishge 256:495. In the case of using the hybridoma method, a mouse, hamster, or other suitable host animal is immunized as described above to induce lymphocyte production of antibodies that will specifically bind to the immunizing antigen. In addition, lymphocytes can be immunized ip miigo. After immunization, lymphocytes are isolated and fused with an appropriate myeloma cell line using, for example, polyethylene glycol to obtain hybridoma cells, which can then be separated from unfused lymphocytes and myeloma cells. Hybridomas producing monoclonal antibodies specifically directed against a selected antigen as determined by immunoprecipitation, immunoblotting, or ip migo binding assay (eg, radioimmunoassay (RIA); solid-phase enzyme-linked immunosorbent assay (ELISA)) can then be grown in ip culture using standard methods (cSodipd, Moposiopai

Apiirodiev: Rgipsirieye apa Rgasiise, Asadetis Rgeb55, 1986) or ip mimo as ascites tumors in animals. Next, monoclonal antibodies can be purified from nutrient medium or ascitic fluid as described for polyclonal antibodies above. 00113) Alternatively, monoclonal antibodies can be produced using recombinant DNA techniques as described in US Patent 4,816,567. Polynucleotides encoding the monoclonal antibody are isolated from mature B cells or hybridoma cells, for example by

With the help of RT-PCR with the use of oligonucleotide primers, which specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using conventional methods. The isolated polynucleotides encoding the heavy and light chains are further cloned into appropriate expression vectors in such a way that after transfection of host cells, such as E. soya cells, COB5 monkey cells, Chinese hamster ovary (CHO) cells, or myeloma cells, that themselves do not produce immunoglobulin protein, monoclonal antibodies are generated by host cells. Alternatively, recombinant monoclonal antibodies or fragments thereof from the desired species can be isolated from phage display libraries expressing

SOC of desired species as described (MeoSayepgu ei ai., 1990, Maishge, 348:552-554; SiasKvop ei ai., 1991, Mayte, 352:624-628; and Magkz ei ai!., 1991, 9. Moi . Vioi., 222:581-597).

I00114| Polynucleotide(s) encoding a monoclonal antibody can be further modified in a number of different ways using recombinant DNA technology to generate alternative antibodies. In some embodiments of the invention, the constant domains of the light and heavy chains of, for example, a murine monoclonal antibody, can be substituted 1) for such regions, for example, of a human antibody to generate a chimeric antibody or 2) for a non-immunoglobulin polypeptide to generate a chimeric antibody. In some embodiments of the invention, the constant regions are shortened or deleted to generate the desired fragment of the monoclonal antibody. Site-directed mutagenesis or high density variable site mutagenesis can be used to optimize specificity, affinity, etc. monoclonal antibody. 00115) In some embodiments of the invention, a monoclonal antibody of human anti-

EOIKI is a humanized antibody. In some embodiments of the invention, the humanized antibody is an antibody with a modified surface. In some embodiments of the invention, such antibodies are used therapeutically to reduce antigenicity and responses in the form of HAMA (human anti-mouse antibody) when administered to a human subject.

Humanized antibodies can be produced using a variety of methods known in the art. In some alternative embodiments of the invention, the anti-EOI B1 antibody is a human antibody.

І00116| Human antibodies can be directly obtained using a variety of methods known in the art. Immortalized human B-bo lymphocytes can be obtained, immunized ip myo or isolated from an immunized individual, which produce an antibody directed against the target antigen (see, for example, Soye ei aiYi., Moposiopa! Apiirodiev apa Sapseg TNegaru, Aiap V. I ivv, p. 77 (1985); Voyeteg v. ai., 1991, 9. Ittypoi., 147 (1):86-95; and US patent 5750373). In addition, the human antibody can be selected from a phage library, where such phage library expresses human antibodies, as described, for example, in Matsupai et al., 1996,

May Vioyesn., 14:309-314, Z5peeiv5 ei ai., 1998, Rgos. Magician. Asai. z5si., 95:6157-6162, Noodeproot apa Umipieg, 1991, U. Moi. VioiI., 227:381, and Magk5 ei ai., 1991, 9. Moi. Vioi., 222:581). In addition, methods of generation and use of phage libraries of antibodies are described in US patents Mo 5969108, 6172197, 5885793, 6521404; 6544731; 6555313; 6582915; 6593081; 6300064; 6653068; 6706484; and 7264963; and Koipe ei ai., 2007, 9. Moi. Vio., doii:10.1016/).)1tr.2007.12.018 (each of which is incorporated by reference in its entirety). Affinity maturation and chain shuffling strategies (Magk5 et al., 1992, Bio/Hespoiosdu 10:779-783, incorporated by reference in their entirety) are known in the art and can be used to generate high-affinity human antibodies.

I00117| Humanized antibodies can be obtained from transgenic mice carrying the human immunoglobulin locus, which are able to produce the full spectrum of human antibodies after immunization in the absence of endogenous immunoglobulin production. This approach is described in US patents 5,545,807; 5545806; 5569825; 5625126; 5633425; and 5661016. (00118) The present invention also includes dual-specificity antibodies that specifically recognize ROY K1. Antibodies with dual specificity are antibodies capable of specifically recognizing and binding to at least two different epitopes. Different epitopes can be located within the same molecule (eg, the same BOI K1) or on different molecules, such that both of them, for example, antibodies can specifically recognize and bind to BOI K1, and , for example, with 1) an effector molecule on a leukocyte, such as a T-cell receptor (eg, COZ3) or an Es receptor (eg. СОбА, сО032 or СО16) or 2) a cytotoxic agent, as described in detail below.

IІ00119| Polypeptides according to the present invention can be recombinant polypeptides, natural polypeptides or synthetic polypeptides containing a human anti-EOI B1 antibody or its fragment.

I00120| Polypeptides and analogs can be further modified to contain additional chemical fragments that are not normally part of the protein. Such derivatized fragments can improve the solubility, biological half-life or absorption of the protein. In addition, fragments can reduce or eliminate any desired side effects of proteins, etc. An overview of such fragments can be found in KEMIMSTOMYE RNAKMASETSSHTISAI.

ZSIEMSE5, 201p unit., Mask Rybiizpipd So., Eaviop, RA (2000). 00121) Methods known in the art for purifying antibodies and other proteins further include, for example, those described in US Patent Publications Mo. 2008/0312425, 2008/0177048, and 2009/0187005, each of which is hereby incorporated by reference. by reference in its entirety.

I. Immunoconjugates 00122) Methods of administration of conjugates containing anti-ROI K1 antibodies, antibody fragments and their functional equivalents, as disclosed herein, bound or conjugated to a drug or prodrugs (also designated in herein as immunoconjugates) are also described herein. Suitable drugs or prodrugs are known in the art.

Drugs or prodrugs can be cytotoxic agents. The cytotoxic agent used in the cytotoxic conjugate of the present invention can be any compound that causes or induces cell death or otherwise reduces cell viability, and includes, for example, maytansinoids and maytansinoid analogs.

Other suitable cytotoxic agents are, for example, benzodiazepines, taxols, analogues

Сб-1065 and СС-1065, duocarmycins and duocarmycin analogs, enediins such as calicheamicins, dolastatin and dolastatin analogs, including auristatins, tomymycin derivatives, leptomycin derivatives, methotrexate, cisplatin, carboplatin, daunorubicin, doxorubicin, vincristine, vinblastine, melphalan, mitomycin C, chlorambucil and morpholinodoxorubicin. 00123) Such conjugates can be obtained using a linker group to connect a drug or prodrug with an antibody or functional equivalent. Suitable linker groups are well known in the art and include, for example, disulfide groups, thioether groups, acid-labile groups, photolabile groups, peptidase-labile groups and esterase-labile groups. 00124) The drug or prodrug can, for example, be combined with an anti-

ROKI or its fragment using a disulfide bond. The linker molecule or cross-linking agent contains a reactive chemical group that can react with the anti-ROI K1 antibody or its fragment. Reactive chemical groups for reaction with cell binding agent 3 can be M-succinimidyl esters and /-M-sulfosuccinimidyl esters. In addition, the linker molecule contains a reactive chemical group, which can be a dithiopyridyl group and can react with the drug to form a disulfide bond. Linker molecules include, for example, M-succinimidyl-3-(2-pyridyldithio)propionate (5POP) (see, e.g., Sagi5zop et al., Biospet. 5., 173: 723-737 (1978)), M-succinimidyl -4-(2-pyridyldithio)butanoate (ZROV) (see, for example, US Pat. No. 4,563,304), M-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-5ROV) (see Publication

USA Mo 20090274713), M-succinimidyl-4-(2-pyridyldithio)pentanoate (5PP) (see, for example, registration number SABZ 341498-08-6), 2-iminothiolane or acetylsuccinic anhydride.

For example, an antibody or cell binding agent can be modified with cross-linking reagents, and the resulting antibody or cell binding agent containing free or protected thiol groups is further reacted with disulfide or thiol-containing maytansinoid to obtain the conjugate. The conjugate can be purified by chromatography, including, but not limited to, HPLC, exclusion, adsorption, ion exchange and affinity capture, dialysis, or tangential flow filtration. 00125) In another aspect of the present invention, the anti-POII K1 antibody is linked to a cytotoxic drug by means of a disulfide bond and a polyethylene glycol spacer to increase the activity, solubility, or efficacy of the immunoconjugate. Such cleavable hydrophilic linkers are described in UMO2009/0134976. An additional advantage of this linker design is the desired high monomer ratio and minimal aggregation of the antibody-drug conjugate. Specifically included in this aspect are conjugates of cell-binding agents and drugs linked by means of a disulfide group (-5-5-) carrying polyethylene glycol spacers (СНеСНгО)пп-1-14) with a narrow interval of drug loading 2-8, which are described as exhibiting high biological activity against cancer cells and having the desired biochemical properties of high conjugate yield and high monomer ratio with minimal protein aggregation. 00126) In addition, it is possible to obtain an antibody-maytansinoid conjugate with non-cleavable linkers. Such crosslinking agents are described in the art (see US Publication Mo

Zo 20050169933) and include, but are not limited to, M-succinimidyl-4-(maleimidomethyl)cyclohexanecarboxylate (ZMOSS). In some variants of implementation of the invention, the antibody is modified with the help of cross-linking reagents, such as succinimidyl-4-(M-maleinimidomethyl)-cyclohexane-1-carboxylate (5MCS), sulfo-5MCOS, maleinimidobenzoyl-

M-Hydroxysuccinimide ester (MV5), sulfo-MV5 or succinimidyl iodoacetate as described in the literature to introduce 1-10 reactive groups (uUo5pyake ei ai, Yenshg. U. Viospet., 101:395-399 (1979); Nazpiada ei ai, U. Arriei Viospet., 56-63 (1984); and im ei ai, Viospet., 18:690-697 (1979)).

Next, the modified antibody is reacted with a thiol-containing derivative of maytansinoid to obtain a conjugate. The conjugate can be purified by gel filtration through a Zerpadeh 525 column or by dialysis or tangential flow filtration. The modified antibodies are treated with thiol-containing maytansinoid (1-2 molar equivalents/maleimido group) and the antibody-maytansinoid conjugate is purified by gel filtration through a Zerpadeh 0-25 column, chromatography on a ceramic hydroxyapatite column, dialysis, or tangential flow filtration, or a combination of these methods . Of course, on average, 1-10 maytansinoids are bound to the antibody.

One way is to modify the antibodies with succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (ZMSOCC) to introduce maleimido groups, followed by reacting the modified antibody with a thiol-containing maytansinoid to give a thioester-linked conjugate Conjugates containing 1-10 drug molecules per antibody are formed again. Conjugates of maytansinoids and antibodies, fragments of antibodies and other proteins are obtained in the same way.

I00127| In another aspect of the invention, the anti-ROI K1 antibody is linked to the drug by means of a non-cleavable bond through an intermediate PEG spacer. Suitable cross-linking reagents containing hydrophilic PEG chains that form linkers between the drug and the anti-ROI K1 antibody or fragment are also well known in the art or are commercially available (eg, from Cocapia Viodezidp, Powell, OH). In addition, suitable

PEG-containing crosslinkers can be synthesized from commercially available PEGs using standard chemical synthesis methods known to those skilled in the art.

Medicinal products can be reacted with PEG-containing bifunctional cross-linkers to produce compounds of the following formula, 2-X1-(-CH2-CNeg-O-)p-Xr-O, by methods described in detail in US Patent Publication 20090274713 and M/O2009/0134976, which can then be reacted with a cell-binding agent to obtain a conjugate.

Alternatively, cell binding can be modified with a bifunctional PEG cross-linker to introduce a thiol-reactive group (such as maleinimide or haloacetamide), which can then be treated with a thiol-containing maytansinoid to give the conjugate. Alternatively, cell binding can be modified with a bifunctional PEG cross-linker to introduce a thiol moiety, which can then be treated with a thiol-reactive maytansinoid (such as a maytansinoid bearing a maleinimide or haloacetamide) to give con' Yugat (00128) Examples of suitable PEG-containing linkers include linkers containing a

M-succinimidyl ester or M-sulfosuccinimidyl ester for reaction with anti-POI K1 antibody or its fragment, as well as a fragment based on maleimido or haloacetyl for reaction with the compound. The PEG spacer can be introduced into any crosslinking linker known in the art by the methods described herein. 00129) In some embodiments of the invention, the linker is a linker that contains at least one charged group, as described, for example, in US Patent Publication Mo 2012/0282282, the contents of which are incorporated herein by reference in their entirety. In some embodiments of the invention, charged or pro-charged crosslinkers are linkers containing sulfonate, phosphate, carboxyl, or quaternary amine substituents that substantially increase the solubility of the modified cell-binding agent and cell-binding agent conjugates -drug, especially for monoclonal antibody-drug conjugates with 2-20 bound drug/antibody molecules. Conjugates are obtained on the basis of linkers containing a pro-charged fragment, which gives one or more charged fragments after the metabolism of the conjugate in the cell. In some embodiments of the invention, the linker is selected from the group consisting of: M-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoate (sulfo-5PP) and M-succinimidyl-4-(2-pyridyldithio)-2-sulfobutanoate ( sulfo-5ROV). 00130) Many of the linkers disclosed herein are described in detail in US Patent Publications MO 2005/0169933, 2009/0274713 and 2012/0282282, and in UMO2009/0134976; the contents of which are incorporated herein in their entirety by reference. 00131) This invention includes aspects in which from about 2 to about 8 molecules of drug

From the drug ("drug load"), for example, maytansinoid, bound to the anti-ROI KI antibody or its fragment. "Drug loading" as used herein refers to the number of drug molecules (eg, maytansinoid) that can be attached to a cell-binding agent (eg, anti-BOI K1 antibody or fragment thereof). In one aspect, the number of drug molecules that can be attached to the cell binding agent can average from about 2 to about 8 (eg, 1,9,2,0,21,22,2,3,24 ,2,5,2,6,2,7,2,8,2,9, 3,0, 3,1, 3,2, 3,3, 3,4, 3,5, 3,6, 3 ,7, 3,8,3,9,4,0,4,1,42,4,3,4,4,4,5,4,6,4,7,4,8,4,9,5 ,0, 5,1, 5,2, 5,3, 5,4, 5,5, 5,6, 5,7, 5,8, 5,9,6,0,6,1,6,2 ,6,3,6,4,6,5,6,6,6,7,6,8,6,9, 7,0, 7,1, 7,2, 7,3, 7,4, 7 ,5, 7,6, 7,7, 7,8, 7,9, 8,0, 8,1).

You can use M2'-desacetyl-M2'-(3-mercapto-1-oxopropyl)y-maytansine (OM1) and M2-desacetyl-M2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (OM ). 00132) Thus, in one aspect, the immunoconjugate contains 1 maytansinoid per antibody. In another aspect, the immunoconjugate contains 2 maytansinoids per antibody. In another aspect, the immunoconjugate contains C maytansinoids per antibody. In another aspect, the immunoconjugate contains 4 maytansinoids per antibody. In another aspect, the immunoconjugate contains 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains 6 maytansinoids per antibody. in another aspect, the immunoconjugate contains 7 maytansinoids per antibody. In another aspect, the immunoconjugate contains 8 maytansinoids per antibody. 00133) In one aspect, the immunoconjugate contains from about 1 to about 8 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 7 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 6 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 2 to about 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 3 to about 5 maytansinoids per antibody. In another aspect, the immunoconjugate contains from about 3 to about 4 maytansinoids per antibody. 00134) In one aspect, the composition comprising immunoconjugates contains on average from about 2 to about 8 (eg, 1,9,2,0,2,1,2,2,2,3,2,4,2 ,5,2,6,2,7,2,8,2,9, 3,0, 3,1, 3,2, 3,3, 3,4, 3,5, 3,6, 3,7 , 3,8, 3,9,4,0,4,1,4,2,4,3, 4,4, 4,5, 4,6,4,7,4,68,4,9,5 ,0,5,1, 5,2, 5,3, 5,4, 5,5, 5,6, 5,7, 5,8,5,9,6,0,6,1,6,2 ,6,3,6,4,6,5,6,6,6,7,6,8,6,9, 7,0, 7,1, 7,2, 7,3, 7,4, 7 ,5, 7,6, 7,7, 7,8, 7,9, 8,0, 8,1) of attached drug molecules (for example, maytansinoids) to the antibody. In one aspect, the composition containing immunoconjugates contains on average from about 1 to about 8 molecules of drug (eg, maytansinoids) per antibody. In one aspect, the composition containing immunoconjugates contains on average from about 2 to about 7 molecules of drug (eg, maytansinoids) per antibody. In one aspect, the composition containing immunoconjugates contains on average from about 2 to about 6 molecules of the drug (eg, maytansinoids) per antibody. In one aspect, the composition containing immunoconjugates contains on average from about 2 to about 5 molecules of the drug (eg, maytansinoids) per antibody. In one aspect, the composition containing immunoconjugates contains on average from about 3 to about 5 molecules of drug (eg, maytansinoids) per antibody. In one aspect, the composition containing immunoconjugates contains on average from about 3 to about 4 molecules of drug (eg, maytansinoids) per antibody.

I00135| In one aspect, the composition comprising the immunoconjugates contains an average of about 20.5, about 350.5, about 450.5, about 520.5, about 620.5, about 750.5, or about 8:0.5 of attached drug molecules (for example, maytansinoids) to the antibody.

In one aspect, the composition containing immunoconjugates contains an average of about 3.5:20.5 drug molecules (eg, maytansinoids) per antibody. (00136) The anti-OIK1 antibody or its fragment can be modified by introducing a bifunctional cross-linking reagent into the reaction with the anti-ROI K1 antibody or its fragment, thereby providing covalent attachment of the linker molecule to the anti-ROI KI antibody or its fragment. As used herein, a "bifunctional cross-linking reagent" is any chemical moiety that covalently binds a cell binding agent and a drug, such as the drugs described herein. In another method, part of the linker fragment is provided by the drug. In this case, the drug contains a linker fragment that is part of a larger linker molecule used to connect the cell-binding agent to the drug. For example, to obtain maytansinoid ЮОМ', the side chain in the C-3 hydroxyl group of maytansine is modified so that it contains a free sulfhydryl group (ZH). This thiolated form of maytansine can be reacted with a modified cell binding agent to form a conjugate. Thus, the final linker is assembled from two components, one of which provides the cross-linking reagent, while the other is provided by the OM'1 side chain.

I00137| In addition, drug molecules can be linked to antibody molecules using an intermediate carrier molecule, such as serum albumin.

II00138| As used herein, the term "linked to a cell-binding agent" or "linked to an anti-ROI CI antibody or fragment" refers to a conjugate molecule that contains at least one drug derivative bound with a cell binding agent anti-ROI K1 antibody or fragment through a suitable linker group, or its precursor. The linker groups given as an example are 5ROV or sulfo-

Level 00139) In some embodiments of the invention, cytotoxic agents suitable for the present invention are maytansinoids and maytansinoid analogs. Examples of suitable maytansinoids include maytansinol esters and maytansinol analogs. Included are any drugs that inhibit microtubule formation and are highly toxic to mammalian cells, such as maytansinol and maytansinol analogs.

ІІ00140| Examples of suitable maytansinol esters include those containing a modified aromatic ring and those containing modifications in other positions. Such suitable maytansinoids are disclosed in US Pat. Nos. 4,424,219; 4256746; 4294757; 4307016; 4313946; 4315929; 4331598; 4361650; 4362663; 4364866; 4450254; 4322348; 4371533; 5208020; 5416064; 5475092; 5585499; 5846545; 6333410; 7276497 and 7473796.

І00141| In a certain embodiment of the invention, thiol-containing maytansinoid (OOM1), formally named M2-desacetyl-M2-(3-mercapto-1-oxopropyl)-maytansine, is used as a cytotoxic agent in immunoconjugates according to the invention. OMI is represented by the following structural formula (1):

so on ; ; I. y y Y zn

And oh oh

M. Y. "o.

MeO and M; KZ h (I and sha A pi NI: Me: .

Meo HO nn I: (00142) In another embodiment of the invention, thiol-containing maytansinoid, /M"-desacetyl-M2(4-methyl-4-mercapto-1-oxopentyl)-maytansin 5 ( for example, OMA) as a cytotoxic agent. OMA is represented by the following structural formula (I): their : " BA

She

Z o me i M ki , k (Z | y chyv mm o meo no Y 00143) Another maytansinoid containing a side chain that contains a sterically restrained thiol bond is M2-desacetyl-M-2(4-mercapto -1-oxopentyl)-maytansine (named pMm3), represented by the following structural formula (PP):

Oh ich, lk VN her them about mes. I -IG ke she: I U v'MYA so

EE ON

MeO Shsh (00144) Each of the maytansinoids disclosed in US Patent Nos. 5,208,020 and 7,276,497 may additionally be used in the conjugate of this invention. Accordingly, the entire disclosures of 5208020 and 7276697 are incorporated herein by reference.

I00145| Numerous positions on maytansinoids can serve as positions of a chemical bond with a linker fragment. For example, a C-3 position containing a hydroxyl group, a C-14 position modified with a hydroxymethyl group, a C-15 position modified with a hydroxy group, and a C-20 position containing a hydroxy group may be useful. In some embodiments of the invention, the C-3 position serves as the position of the chemical bond with the linker fragment, and in some specific embodiments of the invention, the C-3 position of maytansinoid serves as the position of the chemical bond with the linker fragment. (00146) The structural representation of some conjugates is given below: p so

І - от І о. х Eх и и р; and Ch

With a and cheeks She ya mch ya ke ba. more. And where are 2 hz OA months. Hmm A A B - a. She

Ii same E " i a Ii : I g y i Mo Ave Antitio mes OO shk -

And and and VK ee Nabo Me

Oma: Ved

Oma ve SnIdeya kov 1st b -V

BUT mMav Om LmYA tu t 00 E.O 7

NE o i ut, vi n ah 5 Ko mi mit Ar sche che A i sho V - r

TV and - CM TO AB- Antnytilo mes NO: - va

AV-IEGYA- Ma-TyMIi U sh- E o. Hey and a at 8 DO kt Mllya Ar a oo | and p

Mao Yak au SHY in o h ri Kz y g Qi

EE where | DM I 5 ma mes NO N DiB-Antibody

KE - NapoMme om: VN,

PMmA: in- SN, d-o pe 1-24 pcs

AVPEGOZALOMO LIMA khz z h o t y od - S 1 9 -

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IN

: and weight | Not AB - Antibody mes? not H 7 8-5 d-VMSS-OMI

B and dk with Ka Zh N Ar wines with she; by in ad: o y

May a

Beh KZ r. U

SHY si ach y. r o M iv mes" NO sn

AB - Antichtina zv d'-CHIA-HMI M v o o Zh V. zr shi | m dv

Y and Z | | NN in min o I-3 - Z A Ap Avprintsu may na nn - TYA) bod y Nd, m Band MepAV "SHE /x ІІ

Mes M; in the grove 7 Av -Antnti - kt g sin CHI A Antnticha

EOM o mes" no nn 3-5 dej-BErV-rmA x in Z

Av-dntitya

В) ze KT» x Ye ee She « det more and ze VE, . i E Ky x y | : ha And they ee zh i k shiya i sh- A, Kk , . ke o | and Z Ar Ave:

She o MyeV' yo ME. What's wrong:

She a: le Pharmapentically: and not her X prinyuva salt:

B still eh

Archeulfo YAVNYM ov

J

I00147| In addition, the present invention includes any stereoisomers and their mixtures for any compounds or conjugates represented by any of the structures above.

I00148| Several descriptions of the preparation of such antibody-maytansinoid conjugates are provided in US Pat.

I00149| In general, a solution of the antibody in an aqueous buffer can be incubated with a molar excess of maytansinoids containing a disulfide moiety that carries a reactive group. The reaction mixture can be quenched by adding an excess of an amine (such as ethanolamine, taurine, etc.). Further, the maytansinoid-antibody conjugate can be purified by gel filtration.

ИО0О150| The number of maytansinoid molecules bound to the antibody molecule can be determined by spectrophotometric determination of the optical density ratio at a wavelength of 252 nm and 280 nm. The average number of maytansinoid molecules/antibody can be, for example, 1-10 or 2-5. The average number of maytansinoid molecules/antibody can be, for example, about 3 to about 4. The average number of maytansinoid molecules/antibody can be about 3.5 00151) Conjugates of antibodies with maytansinoid or other drugs can be evaluated for their ability to inhibit the proliferation of a variety of unwanted cell lines. applied to evaluate the cytotoxicity of such compounds. The cells to be evaluated can be exposed to the compounds for 4-5 days and the surviving cell fractions measured in direct assays by known methods.

ISvo can be calculated based on the results of the analysis.

I00152| Immunoconjugates can, in accordance with some variants of implementation of the invention described in this document, be internalized by cells. Thus, the immunoconjugate can have a therapeutic effect if it is taken up, or internalized, by a ROI K1-expressing cell. In some specific embodiments of the invention, the immunoconjugate contains an antibody, an antibody fragment, or a polypeptide conjugated to a cytotoxic agent according to

With the help of a cleavable linker, the cytotoxic agent is cleaved from the antibody, antibody fragment or polypeptide after internalization of the BOI by the K1-expressing cell. 00153) In some variants of implementation of the invention, immunoconjugates are capable of reducing tumor volume. For example, in some embodiments of the invention, treatment with the immunoconjugate results in a 95T/C value of less than about 50 95, less than about 45 95, less than about 40 95, less than about 35 95, less than about 30 95, less than about 25 to, less than about 20 95, less than about 15 95, less than about 10 95, or less than about 5 95. In some specific embodiments of the invention, immunoconjugates can reduce tumor size in a xenograft model of KV, OMSAK- 3, I2VOU-1 and/or OU-90. In some embodiments of the invention, immunoconjugates are capable of suppressing metastases.

I. Methods of introduction of ROI K1-binding agents

І00154| BOY A1-binding agents (in particular antibodies, immunoconjugates and polypeptides) according to the invention are suitable for various fields of application, in particular, but not limited to, therapeutic methods of treatment, such as the treatment of cancer. In some embodiments of the invention, the agents are suitable for inhibiting tumor growth, inducing differentiation, inhibiting metastases, reducing tumor volume, and/or reducing tumorigenicity of the tumor. The methods of application can be methods of ip mimo. 00155) According to the methods described in this document, BOI K1-binding agents can be administered in specific doses. For example, BOI K1-binding agents (eg, IMOM 853) can be administered at a dose of from about 0.15 mg/kg to about 7 mg/kg, with kg of body weight resulting in ideal body weight (IBW), dry weight body weight (I VUM), or adjusted ideal body weight (ABU or AIIVMU). In some variants of implementation of the invention BOY K1-binding agents (for example,

IMOMa853) is administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg, while kilograms of body weight lead to IVUM, I VUM or AIVU (ABU). In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg, with kilograms of body weight leading to IVMU, I VUM, or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 0.15 mg/kg, while kilograms of body weight lead to IVUM, GVUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 0.5 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 1.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 1.1 mg/kg, with kilograms of body weight leading to IVUU, GVUM, or AIVUM (AbBU)). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 1.5 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 1.8 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 2.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 2.5 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUU (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 2.8 mg/kg,

At the same time, kilograms of body weight lead to IVMU, I VUM or AIVMU (AbBU)). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 3.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 3.3 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some variants of implementation of the invention, Swarm K1-binding agents (for example, IMOM853) are administered at about 3.75 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 4.2 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 4.5 mg/kg, while kilograms of body weight lead to IVUM, I VUU or AIVUM (ABU)). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 4.8 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 5.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 5.5 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 5.6 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUU (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVMU (AbBU)). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.1 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.2 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVUM (AB). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.3 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.4 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVUM (ABU). In some variants of implementation of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.5 mg/kg, because at the same time kilograms of body weight lead to IVUU, AND! VMU or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.6 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.7 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.8 mg/kg, while kilograms of body weight lead to IVUM, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 6.9 mg/kg, while kilograms of body weight lead to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered at about 7.0 mg/kg, while kilograms of body weight lead to IVMU, I VUM, or AIVMU (AbBU)). In some variants of implementation of the invention, kilograms of body weight lead to AIVUM (ABU). 00156) In addition, ROI B1-binding agents can be administered in a specific range of doses.

For example, ROI K1-binding agents can be administered from about four times a week to about once every four weeks. Thus, in some variants of implementation of the invention, BOY K1 binding agents are administered once every three weeks. In some variants of implementation of the invention, ROI K1 binding agents are administered about once every two and a half weeks. In some variants of implementation of the invention, BOY K1-binding agents are administered about once every two weeks. In some variants of implementing the invention, BOY K1-binding agents are administered about once every ten days. In some embodiments of the invention, Swarm K1-binding agents are administered about once a week. 00157) ROI AB1-binding agents can be administered in a cycle lasting about 3 weeks (ie about 21 days). For example, ROY K1-binding agents can be administered twice over a period of about 3 weeks. Thus, in some embodiments of the invention, Swarm K1-binding agents can be administered on days around 1 and 8 of a 21-day cycle. In other embodiments of the invention, BOY K1-binding agents can be administered three times over a period of about 3 weeks. Thus, in some embodiments of the invention, BOY K1-binding agents can be administered on days around 1, 8, and 15 of a 21-day cycle. 00158) ROI A1-binding agents can be administered in a cycle lasting about 4 weeks (ie about 28 days). For example, ROI K1-binding agents can be administered three times over a period of about 4 weeks. Thus, in some embodiments of the invention, BOY K1-binding agents can be administered on days about 1, 8, and 15 of a 28-day cycle. 00159) In accordance with the methods described in this document, ROI K1-binding agents can be administered in specific doses. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) can be administered at a dose of about 0.15 mg/kg to about 7 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (for example, IMOM853) are administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (for example, IMOM853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (eg, IMOM853) are administered at about 0.15 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 0.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (eg, IMOM853) are administered at about 1.0 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 1.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (eg, IMOM853) are administered at about 1.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, EOIK1-binding agents (eg, IMOM853) are administered at about 1.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some variants of implementation of the invention

EOI A1-binding agents (eg, IMOM853) are administered at about 2.0 mg/kg once a week for three weeks according to a four-week schedule. In some embodiments of the invention, EOY K1-binding agents (for example, IMOM853) are administered at about 2.5 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 2.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (for example, IMOM853) are administered about 60 3.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (eg, IMOM853) are administered at about 3.3 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 3.75 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (eg, IMOM853) are administered at about 4.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 4.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some variants of implementation of the invention

EOI A1-binding agents (eg, IMOM853) are administered at about 4.8 mg/kg once weekly for three weeks in a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (for example, IMOM853) are administered at about 5.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 5.5 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 5.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (eg, IMOM853) are administered at about 6.0 mg/kg once a week for three weeks according to a four-week regimen. In some embodiments of the invention, Swarm K1-binding agents (eg, IMOM853) are administered at about 6.1 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.2 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.3 mg/kg once a week for three weeks in accordance with a four-week regimen. In some variants of implementation of the invention

EOI A1-binding agents (eg, IMOM853) are administered at about 6.4 mg/kg once weekly for three weeks in a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (eg, IMOM853) are administered at about 6.5 mg/kg once per

From a week for three weeks in accordance with the four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.6 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.7 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.8 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 6.9 mg/kg once a week for three weeks in accordance with a four-week regimen. In some embodiments of the invention, EOY K1-binding agents (eg, IMOM853) are administered at about 7.0 mg/kg once a week for three weeks in accordance with a four-week regimen. 00160) According to the methods described herein, ROY K1-binding agents (eg, IMOM853) can be administered at a dose of from about 0.15 mg/kg to about 7 mg/kg once weekly for three weeks, respectively to a four-week regime, while kg of body weight leads to ideal body weight (IWMU), dry body weight (I VUM), or adjusted ideal body weight (AS) or AIVUM) In some variants of the implementation of the invention EOY K1-binding agents ( e.g. IMOM853) is administered at a dose of about 3.0 mg/kg to about 6.0 mg/kg once a week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVUM, IVUM, or AIVUM (AB. in)). In some variants of implementation of the invention

BO EOY A1-binding agents (eg, IMOM853) are administered at a dose of about 3.3 mg/kg to about 6.0 mg/kg once a week for three weeks according to a four-week regimen, with kilograms of body weight to IVMU, I VUM or AIVUM (ABU). In some embodiments of the invention, Swarm K1-binding agents (e.g., IMOM853) are administered at a dose of about 0.15 mg/kg once a week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVUM, AND VUU or AIVMU (AB.U)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 0.5 mg/kg once a week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, VU, or AIVMU ( ABU)). In some embodiments of the invention, EOY K1-binding agents (e.g., IMOM853) are administered at about 1.0 mg/kg once per week for three weeks according to a four-week regimen, with kilograms

From body weight lead to IVUM, IVUM or AIVUM (AB.u)). In some variants of implementation of the invention

EOI A1-binding agents (eg, IMOM853) are administered at about 1.1 mg/kg once a week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVUM, GVUM, or AIVMU (AB). In some embodiments of the invention, BOY K1-binding agents (eg, IMOM853) are administered at about 1.5 mg/kg once a week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVMU ( ABU). In some embodiments of the invention, BOI K1-binding agents (eg, IMOM853) are administered at about 1.8 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMM, I VUM, or AIVMU (ABU). In some variants of implementation of the invention BOY K1-binding agents (for example,

IMOM853) is administered at about 2.0 mg/kg once a week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVMU, GVUM or AIVUM (ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 2.5 mg/kg once per week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVMU, IVUM, or AIVUU ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 2.8 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 3.0 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 3.3 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABU). In some embodiments of the invention, ROY K1-binding agents (e.g., IMOM853) are administered at about 3.75 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 4.2 mg/kg once weekly for three weeks according to

From a four-week regimen, at the same time, kilograms of body weight lead to IVMU, YVUM or AIVUU (ABu)). In some embodiments of the invention, BOI K1-binding agents (eg, IMOM853) are administered at about 4.5 mg/kg once per week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 4.8 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 5.0 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABU). In some embodiments of the invention, ROY K1-binding agents (e.g., IMOM853) are administered at about 5.5 mg/kg once weekly for three weeks according to a four-week schedule, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 5.6 mg/kg once per week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, IVUM, or AIVUU ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.0 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.1 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.2 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABU). In some embodiments of the invention, ROY K1-binding agents (e.g., IMOM853) are administered at about 6.3 mg/kg once per week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( AB)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.4 mg/kg once per week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, IVUM, or AIVUU

(Abu)). In some embodiments of the invention, BOI K1-binding agents (eg, IMOM853) are administered at about 6.5 mg/kg once per week for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.6 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.7 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABU). In some embodiments of the invention, ROY K1-binding agents (e.g., IMOM853) are administered at about 6.8 mg/kg once per week for three weeks according to a four-week schedule, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 6.9 mg/kg once per week for three weeks in accordance with a four-week regimen, with kilograms of body weight leading to IVMU, IVUM, or AIVUU ( ABu)). In some embodiments of the invention, BOI K1-binding agents (e.g., IMOM853) are administered at about 7.0 mg/kg once weekly for three weeks according to a four-week regimen, with kilograms of body weight leading to IVMU, GVUM, or AIVUM ( ABU)). In some variants of implementation of the invention, kilograms of body weight lead to AIVUM (ABU). 00161) In some variants of the implementation of the invention, BOY K1-binding agents can be administered in a dose that leads to a specific Stakh. For example, in some variants of implementation of the invention

EOY A1-binding agents are administered in a dose that leads to Stach from about 110 to about 160 μg/ml. In some variants of the implementation of the invention, BOY K1-binding agents are administered in a dose that leads to Stach from about 110 to about 150 μg/ml. In some variants of implementing the invention, Swarm K1-binding agents are administered in a dose that leads to Stach from about 110 to about 140 μg/ml. In some variants of implementing the invention, BOY K1-binding agents are administered in a dose that leads to Stach from about 120 to about 160 μg/ml. In some embodiments of the invention, Swarm K1-binding agents are administered in a dose that results in Stach from about 120 to about 150 μg/ml. In some variants of the implementation of the invention, BOY K1-binding agents are administered in a dose that leads to Stach from about 120 to about 140 μg/ml. In some variants of implementing the invention, Swarm K1-binding agents are administered in a dose that leads to Stach from about 90 to about 160 μg/ml. In some embodiments of the invention, BOY K1-binding agents are administered in a dose that results in a Stach of about 90 to about 150 μg/ml. In some variants of the implementation of the invention, Swarm K1-binding agents are administered in a dose that leads to Stach from about 90 to about 140 μg/ml. In some embodiments of the invention, BOY K1-binding agents are administered in a dose that leads to Stach from about 100 to about 160 μg/ml. In some embodiments of the invention, Swarm K1-binding agents are administered in a dose that leads to Stach from about 100 to about 150 μg/ml. In some variants of implementing the invention, BOY K1-binding agents are administered in a dose that leads to Stach from about 100 to about 140 μg/ml. 00162) In some variants of the implementation of the invention, ROG OK1-binding agents can be administered in a dose that leads to a specific AOS. For example, in some variants of implementation of the invention

EOY A1-binding agents can be administered in a dose that leads to AOSo-a4 no more than 2785 h-μg/ml. In some variants of implementing the invention, BOY K1-binding agents can be administered in a dose that leads to ASO-ha no more than 2741 h-μg/ml. In some variants of the implementation of the invention, BOY K1-binding agents can be administered in a dose that leads to AOsCo-g4" no more than 2700 h-μg/ml. In some variants of implementation of the invention, the introduction provides AOSo-ha about 1000-3500 h-μg/ml. In some variants of the implementation of the invention, the introduction provides ASHcSO-2a about 1000-3000 h-μg/ml. In some embodiments of the invention, the introduction provides

ASHSo-ha is about 1000-2785 h-μg/ml. In some variants of implementation of the invention, the introduction provides ASHSo-ha about 1000-2741 h-μg/ml. In some embodiments of the invention, the introduction is provided by AMSogy. about 1000-2700 h-μg/ml. In some variants of implementation of the invention, the input is provided by AMSHSoga. about 1000-2500 h.mcg/ml. In some variants of implementation of the invention, the introduction provides AOSo-ha no more than 1500-3500 h-μg/ml. In some variants of implementation of the invention, the introduction provides AOSo-g4 no more than 1500-3000 h-μg/ml.

In some variants of implementation of the invention, the introduction provides ACo-g4 no more than 1500-2785 h-μg/ml. In some variants of implementation of the invention, the introduction provides AOSo-g" no more than 1500-2741 h.mcg/ml. In some variants of the implementation of the invention, the introduction provides AOsSo-ha no more than 1500-2700 h.mcg/ml. In some embodiments of the invention, the introduction provides

ASHsSO-ha is about 1500-2500 h-μg/ml.

IІ00163| In some embodiments of the invention, the disease that is treated with a K1-binding agent or antagonist (for example, an anti-ROI Kt antibody) is cancer. In some embodiments of the invention, the cancer is characterized by EOY KI1-expressing cells, which are bound by a BOI K1-binding agent (for example, an antibody). In some embodiments of the invention, the tumor overexpresses human ROI K1. 00164) The present invention provides methods of treating cancer comprising administering a therapeutically effective amount of a ROI K1-binding agent to a subject (eg, a subject in need of treatment). Types of cancer that can be treated by the methods included in the invention include, but are not limited to, neoplasms, tumors, metastases, or any disease or disorder characterized by uncontrolled cell growth. Cancer can be primary or metastatic cancer. Specific examples of cancers that can be treated by the methods included in the invention include, but are not limited to, ovarian cancer, lung cancer, colon and rectal cancer, pancreatic cancer, liver cancer, breast cancer, brain cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, and head and neck cancer. In some embodiments of the invention, the cancer is ovarian cancer. In some embodiments of the invention, the cancer is lung cancer. In some cases of implementing the invention, the cancer is small cell lung cancer. In some cases of implementation of the invention, non-small cell lung cancer is a lung adenocarcinoma. 00165) In some embodiments of the invention, the cancer is a cancer that expresses BOI K1 (polypeptide or nucleic acids). In some embodiments of the invention, the ROI K1-binding agent is administered to a patient with increased expression of ROIK, for example, as described in US Published Application Mo. 2012/0282175 or International Published Application M/O 2012/135675, both of which are incorporated herein by reference in its entirety. Thus, in some embodiments of the invention, the expression of ROI KI is measured immunohistochemically (INS) with obtaining scores of intensity of staining and/or scores of uniformity of staining in comparison with a control (for example, a calibrated control), which demonstrates a certain number of points (for example, an intensity score of to the test sample, if the intensity is comparable to the C level of the calibrated control, or intensity 2

Zo is assigned to the test sample, if the intensity is comparable to the level of o 2 of the calibrated control). Color homogeneity, which is heterogeneous or homogeneous, also indicates increased expression of ROI K1. Points for color intensity and color uniformity can be used separately or in combination (for example, 2 homo, 2 hetero, C homo, C hetero, etc.). In another example, increased expression of ROI K1 can be determined by detecting an increase of at least 2-fold, at least 3-fold, or at least 5-fold) relative to control values (eg, the level of expression in a tissue or cell of a subject in which cancer is absent or present cancer, in which the values of ROI KI do not increase). 00166) In some embodiments of the invention, the cancer is a cancer that expresses BOI K1 at the level of 1 hetero or higher according to ANN data. In some embodiments of the invention, the cancer is a cancer that expresses ROI KI at level 2 hetero or higher according to ANN. In some embodiments of the invention, the cancer is a cancer that expresses ROI KI at the level of C hetero or higher according to ANN. In some embodiments of the invention, the cancer is a lung cancer that expresses

EOG KI at level 2 hetero or higher according to INS data. In some embodiments of the invention, the cancer is a lung cancer that expresses ROI KI1 at the C hetero level or higher according to ANN data. In some embodiments of the invention, the cancer is an ovarian cancer that expresses BOI K1 at level 2 hetero or higher according to ANN data. In some embodiments of the invention, the cancer is an ovarian cancer that expresses BOYKI at the C hetero level or higher according to ANN. In some embodiments of the invention, the cancer is an endometrial cancer that expresses BOI KI1 at the level of 1 hetero or higher according to ANN data. In some embodiments of the invention, the cancer is an endometrial cancer that expresses ROI K1 at the level of 2 hetero or higher according to ANN data.

I00167| In some embodiments of the invention, the method of inhibiting tumor growth includes administering to the subject a therapeutically effective amount of a BOY K1-binding agent. In some variants of the implementation of the invention, the subject is a person. In some embodiments of the invention, the subject has a tumor or the tumor has been removed. 00168) In addition, the present invention provides a method of reducing the tumorigenicity of a tumor in a subject, which includes administering to the subject a therapeutically effective amount of ROI K1-binding agent. In some embodiments of the invention, the tumor contains cancer stem cells. In some embodiments of the invention, the incidence of cancer stem cells in a tumor is reduced by administering an agent. because I00169| The present invention additionally provides pharmaceutical compositions containing one or more ROI K1-binding agents described herein. In some embodiments of the invention, pharmaceutical compositions additionally contain a pharmaceutically acceptable carrier. Such pharmaceutical compositions are used to suppress tumor growth and treat cancer in human patients.

ІІ00170| In some embodiments of the invention, preparations are prepared for storage and use by combining a purified antibody or agent of the present invention with a pharmaceutically acceptable carrier (e.g., carrier, excipient) (Ketipdiop, Te Zsiepse apa

Rgasiise oi Rpaptasu 201p Ediiop Mask Rybiizpipo, 2000). Suitable pharmaceutically acceptable carriers include, but are not limited to, non-toxic buffering agents such as phosphate, citrate and other organic acids; salts such as sodium chloride; antioxidants, including ascorbic acid and methionine; preservatives (eg, octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (eg, less than about 10 amino acid residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (for example, 2p-protein complexes); and nonionic surfactants such as TMUUEEM or polyethylene glycol (PEG).

I00171| The pharmaceutical compositions described herein can be administered in any number of ways, for local or systemic treatment. Application may be topical (e.g., to mucous membranes, including vaginal and rectal administration), such as transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders; pulmonary (eg, inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal (and transdermal); oral; or parenteral, including intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection, or

From infusion; or by intracranial (eg, intrathecal or intraventricular) administration. In some specific variants of implementation of the invention, the introduction is carried out intravenously. 00172) The antibody or immunoconjugate may be combined in a pharmaceutical combination preparation or administration regimen, in the form of a combination therapy, with a second compound. In some embodiments of the invention, the second compound is a steroid. In some embodiments of the invention, the methods include the administration of a steroid and an immunoconjugate, which leads to a reduction in headache, compared to the administration of only the immunoconjugate. 00173) The steroid can be administered simultaneously with the immunoconjugate, before the administration of the immunoconjugate and/or after the administration of the immunoconjugate. In some embodiments of the invention, the steroid is administered within about a week, about five days, about three days, about two days, or about one day or 24 hours before the administration of the immunoconjugate. In some embodiments of the invention, the steroid is administered within one day of the administration of the immunoconjugate. In some embodiments of the invention, the steroid is administered multiple times. In some embodiments of the invention, the steroid is administered about one day before the administration of the immunoconjugate and on the same day as the immunoconjugate. The steroid can be administered by any number of routes, including, for example, topical, pulmonary, oral, parenteral, or intracranial administration. In some variants of implementation of the invention, administration is carried out orally. In some variants of implementation of the invention, administration is carried out intravenously. In some variants of implementation of the invention, administration is carried out both orally and intravenously.

I00174| Additionally, the antibody or immunoconjugate may be combined in a pharmaceutical combination preparation or administration regimen, in the form of a combination therapy, with an analgesic or other therapeutic agents that prevent or treat headache. For example, acetaminophen and/or dephenhydramine can be administered in addition to the administration of the antibody or immunoconjugate. The analgesic can be administered before, at the same time, or after the administration of the immunoconjugate, and this can be done by any suitable route of administration. In some embodiments of the invention the pain reliever is administered orally.

IІ00175| In some embodiments of the invention, the methods include the introduction of the first compound, which is an antibody or immunoconjugate, the second compound, which is a steroid, and the third compound, which is an analgesic. In some embodiments of the invention, the methods include administration of the first compound, which is IMOM388, the second compound, which is dexamethasone, and the third compound, which is acetaminophen and/or diphenhydramine. 00176) The antibody or immunoconjugate may be combined in a pharmaceutical combination preparation or administration scheme, in the form of combination therapy, with a second compound having anticancer properties. The second compound in the pharmaceutical combination preparation or administration scheme may have complementary activity to the AOS of the combination in such a way that they do not exert an adverse effect on each other. Additionally, pharmaceutical compositions containing ROI K1-binding agent and a second anticancer agent are proposed. 00177

I00178| Variants of the implementation of the invention in accordance with this document can be further defined with reference to the following non-limiting examples, in which the preparation of some antibodies according to the present invention and methods of using the antibodies according to the present invention are described in detail.

For specialists in this field of technology, it will be obvious that numerous modifications of materials and methods can be made without going beyond the scope of the present invention.

Examples

I00179| It should be understood that the examples and embodiments of the invention described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested by those skilled in the art and should be regarded as falling within the scope of of this invention.

Example 1

Dose trial of IMOSM853 in human patients with cancer

I00180| IMOM853 is an antibody-drug conjugate (AOD) containing an antibody that binds to the folic acid receptor 1 (FAR) and a highly active maytansinoid, OMA. IMOM853 was previously described in International Published Applications MO 2011/106528, UMO 2012/135675 and UMO 2012/138749, and US Published Applications Mo 2012/0009181, 2012/0282175 and 2012/0282282, each of which is incorporated herein by reference. in full. IMOM853 is piMom19-55P08-OM4, and the piMom19 antibody contains a variable heavy chain with the amino acid sequence 5EO IU MO: C and a variable light chain with the amino acid sequence 5EBO IU MO: 5. BOI K1 protein is expressed at elevated levels in many solid tumors, especially epithelial

From ovarian cancer (EOS), endometrial cancer, non-small cell lung cancer (NSCLC) and clear cell kidney cancer.

I00181| A maximum tolerated dose (MTD) and phase 2 recommended dose (MRD) study was initiated to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PDO) and efficacy of IMOM853. The study includes two parts: an accelerated dose titration part, where IMOM853 immunoconjugate was administered to patients with any type of BOIK1I-expressing solid tumors that are difficult to treat, including epithelial ovarian cancer (EOC) and other ROY K1-positive solid tumors; as well as part of the dose increase. 00182) In the accelerated titration portion of the study, IMOM853 was administered intravenously (IM) on day 1 of each 21-day cycle (Week 3). Twenty-nine patients were enrolled in the study for seven dose levels ranging from 0.15 to 7.0 mg/kg

IMOM853 is in the accelerated part of the clinical trial of the drug and reliable data are available at this time for 23 patients. There are no studies of adverse drug-related effects of any degree in the first 4 groups of patients. Adverse events associated with IMOM853 at a dose of 5.0 mg/kg were mild to moderate. In doses of 5.0 and 7.0 mg/kg, ophthalmic toxicity was noted in 4 out of 10 in 5 out of 5 patients, respectively.

Table 1

Inclusion in the study by tumor type

Diagnosis

Ovarian cancer 2 2 7 4 1 16

Serous 1! 6" out of 10

Transitional cell 12 1

Clear cell 1 1 1 Z

Carcinosarcoma 1 14 1

Endometrial 2 5 1 8

Serous Z 1 4

Endometrioid 2 2

Adenosquamous 1 1

Mixed 1 1 shen 115

NMRL of the United States 7 HH 11

Clear cell 2 25 4 1 CA125 response in 1 patient for each 3.3 mg/kg, 5.0 mg/kg and 7.0 mg/kg 2 Confirmed partial response

C Unconfirmed partial response and confirmed CA 125 response in 1 patient at 5.0 mg/kg

Cellular » Negative

I00183| The area under the pharmacokinetic curve of the drug was measured in 23 patients and found to generally increase linearly, with a half-life at 5 doses of 2.0 mg/kg of about 5 days. One patient with serous endometrial cancer also had a CA125 response and an unconfirmed partial response to 5 mg/kg. In three patients with ovarian cancer, a confirmed CA125 response was registered (one each at doses of 7 mg/kg, 5 mg/kg and one at 3.3 mg/kg). Patients receiving IMOM853 at doses greater than or equal to 5.0 mg/kg received dexamethasone 10 mg IV (or equivalent steroid) 30 to 60 minutes prior to administration of the anti-ROI CI immunoconjugate (e.g. , IOM853).

I00184| Pharmacokinetic (PK) parameters are shown for Cycle 1 (only the first cycle of administration for each patient) of the Phase 1 IMOM853 trial (Figures TA and B). It is shown that the clearance of IMOM853 is fast at low doses (Ci - 1.1 ml/h/kg) with a half-life of about 35.4 hours or 1.5 days. Clearance decreases (Ci - 0.4 ml/h/kg) at higher doses, and at doses of 2 2.0 mg/kg the half-life increases to about 4 days or about 5 days. It is shown that the area under the pharmacokinetic curve (PKC) and Cmax at higher doses, in general, also increase. 00185) For the 7.0 mg/kg dose, all 5 patients experienced ophthalmic toxicity. In one patient, grade C dose-limiting punctate keratitis and grade 2 visual opacities were reported, which are considered definitely related to the study treatment. In addition, grade C, grade 2, and grade 1 visual opacities were registered in 1 patient for each; all cases are considered possibly or definitely related to IMOeM853 treatment. As a result, the maximum tolerated dose with this administration schedule (ie, once every three weeks) was considered to be exceeded at the 7.0 mg/kg dose level, and for all patients receiving the 7.0 mg/kg dose, the was reduced to the previous level (5.0 mg/kg) and 7 other patients were evaluated at a dose of 5 mg/kg. Together with 3 patients who were treated earlier, 10 patients received treatment at a dose of 5 mg/kg. A total of 10 patients at the 5 mg/kg dose level had blurred vision, including 1 patient with 3 degrees of blurred vision, and 2 patients had corneal changes. Other associated grade C adverse events included elevated alkaline phosphatase and grade 3 hypophosphatemia. Additional patients are included in the study at a dose level of 3.3 mg/kg to further confirm the safety profile observed in 3 patients initially assigned this dose. Safety analysis of the other 6 patients, who are currently being treated at 3.3 mg/kg and IMOM853 is well tolerated. To date, three of nine patients treated at 3.3 mg/kg have experienced IMOM853-related adverse events, including grade 2 peripheral neuropathy (1 patient), grade 2 nausea, fatigue, and increased AST (1 patient), and 1 patient with 2nd degree vomiting. (00186) Once the MTO is determined, the study will enter the drug therapy phase at the dose reached during the maximally tolerated dose escalation phase. In three groups of therapy with the drug at the dose reached during the phase of increasing the dose of the drug to the maximum tolerated, patients with ROY K1-protein positive (1) platinum-resistant epithelial ovarian cancer will be evaluated; (2) relapsed or refractory epithelial ovarian cancer, and (3) relapsed or refractory non-small cell lung cancer (NSCLC).

Cohorts 2 and C will include evaluation of IMOM853 RO by pre- and post-dose tumor biopsy and/or RI .T-PET imaging, respectively. IMOM853 will be administered at a dose of at least 3.3 mg/kg and possibly include doses of 5.0 mg/kg, or even as high as 6.0 mg/kg or even 7.0 mg/kg. Initially, IMOM853 should be administered at a rate of 1 mg/min; after 30 minutes, the rate can be increased to 3 mg/min, provided it is well tolerated. In the case of good tolerability, after 30 minutes of administration at a rate of 3 mg/min, the rate can be increased to 5 mg/min. Subsequent infusions can be given at a tolerable rate.

I00187| For all IMOM853 doses of 3.3 mg/kg or higher, prophylactic steroid treatment using the protocols described in Example 2 will be included (eg, steroid treatment with 10 mg IV dexamethasone (or equivalent steroid) should be included as 30-60 minutes before the introduction of IMOM853, and prophylactic administration of diphenhydramine NSI and acetaminophen before the introduction of IMOM853 is recommended). Cycles are repeated until (i) the patient's disease worsens, (ii) the patient does not develop unacceptable toxicity, (her) the patient does not withdraw his consent, (im) the patient does not develop a comorbidity that prevents further treatment under study , or (m) the patient's participation in the study will not be terminated due to noncompliance with physician orders or for administrative reasons. 00188) The response is evaluated using the criteria of KESI5ZT and the International Intergroup of Gynecological Cancer (OSI) (depending on the specific case).

Example 2

Steroid-Based IOM853 Infusion Reaction Prophylaxis 00189) Any of the following steroid-based prophylaxis protocols may be used to reduce the likelihood of an infusion reaction. 001901) (1) Patients receive dexamethasone, 10 mg IV (or equivalent steroid), 30-60 minutes before administration of an anti-ROI K1 immunoconjugate (eg, IMOM853). 00191) (2) Patients receive dexamethasone, 10 mg IV (or equivalent steroid) and NSI diphenhydramine (25-50 mg IV or PO), with acetaminophen (325-650 mg IV or PO o) or without it, 30-60 minutes before the administration of the anti-ROI K1 immunoconjugate (for example, IMOM853). This prophylactic protocol is recommended and is at the discretion of each researcher. 00192) (3) Patients receive 8 mg (or equivalent of a similar steroid) dexamethasone orally twice daily on the day preceding administration of an anti-EOI B1 immunoconjugate (eg, IMOM853). On the day of administration of the anti-ROI K1 immunoconjugate (for example, IMOM853), 30-60 minutes before the administration of the anti-ROIK immunoconjugate! (eg, IMOM853) patients receive dexamethasone, 10 mg IV (or equivalent steroid), diphenhydramine NS (25-50 mg IV or SC), with acetaminophen (325-650 mg IV or SC o) or without it. (4) Steroids (eg, dexamethasone) are administered orally within 24 hours before the infusion.

Example C

The relationship between the area under the pharmacokinetic curve (AUC) of IMOM853 and ophthalmic toxicity

IІ00193| For each patient who was treated with IMOM 853 according to the protocol described in examples 1 and 2, the concentration of IMOM853 in plasma was measured at different time points during each cycle, at the beginning and at the end of the infusion and continued to be measured for 21 days. Analysis of pharmacokinetic parameters (PC) revealed a clear relationship between Stach and the occurrence of ophthalmic toxicity, which is characterized by deposits in the cornea and loss of visual acuity. A statistically significant correlation was also observed at the initial levels of exposure, measured by the area under the curve during the first 24 hours (AcSo-ha). (See figures 2A-2B). (00194) In the 3.3 to 7.0 mg/kg groups, ophthalmic toxicity was observed in 9 of 10 patients with Stach values at or above 147.7 μg/mL, as indicated by the dashed line in Figure 2A. There were no patients with Stach values lower than 147.7 μg/ml with detected ophthalmic 60 toxicity. In all (9/9) patients with AOSogy at or above 2785 h-μg/ml,

those indicated by the dashed line in Figure 2B had ophthalmic toxicity, while no patient below the dashed line had ophthalmic toxicity. An effect was observed at doses of 2 to 3.3 mg/kg and did not correlate with reports of ophthalmic toxicity. The lowest value of Stach in patients who had an effect was 91.25 μg/ml. 00195) In 24 patients treated with either 3.3 mg/kg, 5.0 mg/kg, or 7.0 mg/kg IMOM853, C values above the threshold correlated with ophthalmic toxicity (reverse) using Fisher's exact test , p - 0.00004. The value of ASO-g" above the threshold level of 2741 h-μg/ml also correlates with ophthalmic toxicity (werewolf) when applying Fisher's exact test, p - 0.00001. Based on these results and calculations using nominal time and concentration values, it was determined that patients with a Stach greater than about 150 μg/mL or an AsSO-ha value greater than 2785 h-μg/mL were most likely to have an increased frequency ophthalmic toxicity, and patients in whom the effect was noted had a Stach level of at least about 90 μg/mg. Strategies were developed to modify drug regimens to reduce apparent variability within each dose level and achieve Stach 3 with optimal efficacy and minimal toxicity for any patient weight.

Example 4

Alternative methods of application of IMOM853 00196) As described above in example 3, a correlation between values of Stach greater than 150 μg/ml or values of ASCSO-g" greater than 2785 h.μg/ml and the frequency of occurrence of ophthalmic toxicity was observed at all dose levels. In addition, initial analysis of pharmacokinetic parameters showed that although Cmax increases proportionally with IMOM853 dose, there is significant variation in Cmax,

ASHMsSo-ha and the volume of distribution within the permissible doses (Figure 3).

І00197| Changes in Stach are especially noticeable in the 5 mg/kg group, where RK was analyzed in 10 patients. There were no apparent changes in Stach in the same patient across cycles, and infusion times were similar between patients and were not associated with changes in Stach. Analysis of covariance showed a correlation between mass and

Stakh (figure 4).

I00198| Volume of distribution (Mee) is an indicator of blood plasma volume for biological drugs and does not increase linearly with weight. When Stakh values were normalized to M55,

The spread was reduced. These data suggest that by exploring other alternative routes of administration, with the exception of approaches based on total body weight, more uniform dosing may be achieved across the group. To this end, values of Stach were determined using alternative dosage calculations for all patients treated in groups at doses of 3.3 (n - 3), 5.0 (n - 10) and 7 mg/kg (n - 5) . Calculated Cmax values were scaled to a dose of 5 mg/kg and compared with Cmax values obtained from total body weight (TBW) dosing. Body surface area (B5A) was also considered, however, Stach values based on B5A dosing decreased and variability was minimally affected, and a positive correlation between weight and Stach was still observed, albeit to a lesser extent. Three alternative formulas were also evaluated: (1) ideal body weight (IBW), dry body weight (IBW), and adjusted body weight (ABU). The formula for each IVMU, I VUM, ABU and VZA is given below:

Ideal body weight (IBW)

IVUM (person) - 0.9Н-88

IVUM (female) - 09-92 (where H is height in cm)

Dry body weight (I VUM)

Men - 1.10 x mass in kg - 128 (mass in kPe/|100 x height in meters|")

Women: 1.07 x mass in kg - 148 (mass in kPe/|100 x height in meters|-)

Adjusted ideal body weight (AIVUM or ABU)

IVUM - 0.4 (actual mass in kg - IVMU)

Body surface area (B5A) - Mosteller formula

B5A (m3) :- (height (cm) x weight (kg) / 3600) ?

Surface area of bodies (SBA) - Boyd's formula

VZA (m) - (0.0003207 x height (cm)oz x mass (g) 07285 - (0.0188 xIoo(0)) 001991) The average values of Stakh were 93.06, 82.72, 110.77 and 137 ,46 μg/ml for IVMU, AND VUM,

AIVMU (AB) and TVUMU, respectively. In addition, all three alternative indicators reduced the standard deviation in Stach (21.7, 20.5, 22.9 vs. 33.7 μg/ml for TVUM). (See figure 5). (00200) As already mentioned above, a positive correlation of TVUM and Stakh was found. The graph shows that the correlation analysis revealed a negative correlation between IVUM and GVUM with mass.

Dosing by body weight of AIVMU (ABU) had a lower dependence on body weight (see figure 6), similar to VZA, but with less variability of RK. 002011) Dosing according to IVMM, I VUM or AIVUU (АВВ))) leads to the smallest dependence on mass in comparison with dosing according to TVMU. Based on current data, by mass dosage

IVUM (ABU leads to a smaller dispersion Stakh.

I00202| AOSo-gi values were observed in 24 patients who received 3.3, 5 or 7 mg/kg

IOM853 based on total body weight (see figure 7 ""TVUU actual") In addition, the value

АССо-ha was observed in 7 patients who received 5 mg/kg IMOM853 in terms of adjusted ideal body weight (see figure 7 "5 ABU) actual"). These actual values obtained from 24 patients were compared with the predicted values obtained from the same patients if they had received treatment at 5 mg/kg based on total body weight (Figure 7 "TVMU 5 mg/kg") or if they were treated with 5, 5.4 or 6 mg/kg adjusted ideal body weight (Figure 7 "ABU 5 mg/kg", "ABU 5.4 mg/kg" and "ABU 6 mg/kg") . As shown in the table in Figure 7, the administration of 5 mg/kg IMOM853 in terms of AIVUM (ABU) minimizes the number of patients who, according to predictions, will exceed the threshold level of ACo-g4 of 2741 h-μg/ml associated with ophthalmic toxicity. In addition, only 14 95 of 7 patients who received 5 mg/kg IMOM (853 on an Abu basis) achieved AOsCo-24 levels above 2741 h.mcg/ml, whereas 38 90 patients who received 3,3, 5, or 7 mg/kg of IMOM853 in terms of TVUM exceeded this level. Analysis of AOSo-2g4 determined that the application of nominal time and concentration values leads to a level of 2785 h-μg/ml. When recalculation is carried out using real time, there is a slight change in the value of AChSog" and the threshold value is 2741 h-mcg/ml. 00203) Patients were then treated with either 5 mg/kg based on adjusted ideal body weight, b mg/kg based on adjusted ideal body weight, 5 mg/kg based on total body weight, or 7 mg/kg based on total body weight body weight Figure 8 ("Actual") shows the observed values of АСсСО-г4 in these patients, and these values are compared with the predicted values ("Predicted") that would have been obtained if all these patients were treated with 5 mg/kg adjusted for ideal body weight, 6 mg/kg based on adjusted ideal body weight, 5 mg/kg based on total body weight, or

From 7 mg/kg in terms of total body weight. IBA dosing reduced variability in baseline exposure levels and reduced ophthalmic adverse events as shown below in Table 2. Specifically, only one patient receiving 5 mg/kg IBA experienced abnormalities 1 grade vision and three patients receiving 6 mg/kg adjusted ideal body weight experienced grade 1-2 ophthalmic toxicity. In contrast, doses of 5 mg/kg or more based on total body weight were associated with a greater number of patients experiencing ophthalmic adverse events and Grade C ophthalmic adverse events.

Table 2

Described ophthalmic adverse effects (OPE) with dosage in terms of adjusted ideal body weight (all reversible)

IMOM85Z Patients with (mg/kg given | The number of different sleeps is absent | up to the ideal group in grades 1-2 grade Z grade! body weight) OPE 50 11771111 11111101 0 60 | 7 | with | in | 0 | 0 1 Side effects of the 4th degree. 2 One patient reported visual disturbances. 3 2nd degree of blurred vision and punctate keratitis in 1 patient; 2nd degree retinopathy in one patient; and 1st degree blurred vision and floating "flies" in 1 patient.

Example 5

Alternative mode of introduction of IMOM853

I00204| A population pharmacokinetic model was developed, based on the maximum and minimum values (derivatives of the maximum and minimum) of the concentration-time profiles

IMOM853 with a dosing schedule every 3 weeks (with an increasing dose). Pharmacokinetics of IMOM853,

as stated above, apparently linear in the range of studied doses. 00205) This model was applied to simulate the stationary concentration of IMOM853 in the following relevant application schemes:

1 to 2.5 mg/kg every week (10 dose levels in 0.15 mg/kg increments)

2 to 5 mg/kg once every two weeks (10 dose levels in 0.3 mg/kg increments)

1 to 2.5 mg/kg once weekly for four weeks, then once every other week for four weeks (10 dose levels in 0.15 mg/kg increments)

1 to 2.5 mg/kg once weekly for three weeks in a four-week schedule (10 dose levels in 0.15 mg/kg increments)

I00206| A regimen of once weekly for four weeks followed by once every other week for four weeks resulted in the least accumulation over time (ie, an accumulation index of 1), while once weekly regimen resulted in the highest accumulation (ie, the accumulation index was 1.97). Once a week for three weeks in accordance with the four-week regimen as a whole allowed to increase the area under the pharmacokinetic curve up to 3 times, limiting C below the level at which ophthalmic toxicity is observed (table 3).

Table C (mg/kg) (mcg/ml) (mcg/ml) (mcg/ml) (h-mg/ml) once a week for three weeks 38 119 20 Bo 105 according to the four-week regimen

I00207| A population pharmacokinetic model was also applied to simulate a hypothetical population of 500 patients using the Monte Carlo method. Descriptive statistics were obtained in order to determine the dosing regimens in a portion of subjects with Stach "150 μg/ml to optimize the safety profile of IMOM853. In the scheme of using the drug once a week for three weeks, according to the four-week regimen, doses of 1.5, 2.0, and 2.5 mg/kg led 99 95, 95 90, and 90 95 sample members to Stach "150 μg/ml , respectively.

Example 6

Antitumor activity of IP mimo and predicted pharmacokinetics of repeated administration of IMOM853

I00208| The concentration of the intact IMOM853 conjugate in blood plasma administered intravenously at a dose of 10 mg/kg to female CO-1 mice was determined by the enzyme-linked immunosorbent assay method

From the analysis at different time points after the injection. Pharmacokinetic (PC) analyzes were performed using standard algorithms by the model-independent pharmacokinetic method with the help of the program (201) M/pMopip, Professional version 6.1 (Rpakhdiny, Mountain-

View, California). The maximum concentration (Сах), the total area under the concentration-time curve (АШсСо-»), the final elimination half-life (І12), the systemic clearance (СІ) and the volume of distribution in the steady state (М55) were determined. The value of the first-order rate constant to determine the half-life of the conjugate was estimated using concentration data from 1 to 28 days after administration. The value of the first-order rate constant to determine the half-life (Hi72) of the antibody was estimated using concentration data from 1 to 28 days after administration. Based on the measurement results obtained at a dose of 10 mg/kg, pharmacokinetic models were created in UmipMopip using different doses in both single- and multiple-dose administration modes. The obtained parameters were evaluated in comparison with the antitumor activity of IMOM853 at different doses and modes of administration in MCI-H2110 (non-small cell lung cancer, NSCLC) xenografts in female mice with severe combined immunodeficiency.

I00209| When IMOM853 was administered as a single injection, dose-dependent antitumor activity was observed in the MCI-H2110 model. All doses (2.8, 5.6 and 8.5 mg/kg) showed high activity at T/C values of 10 95, but with an increased dose of IMOM853, the number of complete tumor regressions (SC) increased. Predicted pharmacokinetic parameters of blood plasma also showed a dose-dependent increase in Stach (maximum serum concentration), Samo (mean serum concentration) and area under the pharmacokinetic curve (ASHso-vao h). So,

shows the predicted LC-based plasma parameters and the dose-dependent nature of the intensity of action of single doses of IMOM853, as depicted in Figure 9.

II00210| In contrast to the activity of a single dose, the multidose administration regimen

IMOM853 showed that the activity does not depend on Stakh (Figure 10). Administration of IMOM853 at 2.8 mg/kg x W, daily or every 3 days on a schedule (total dose was 8.4 mg/kg), had similar activity to a single administration of IMOM853 at 8.5 mg/kg. Interestingly, the total area under the pharmacokinetic curve (AU) and the mean serum concentration (Samo) of the cOconjugate were comparable among the study groups, while the Cmax was highest in the single 8.5 mg/kg group. The activity observed with multiple therapeutic exposures suggests that this dosing method has greater activity, as there were tumor-free animals to the end of the study compared to the absence of tumor-free animals in the single dose group. 00211) In addition, doses of IMOM853 and application regimens were evaluated for activity against MCI-H2110 xenografts, according to the results, consistently demonstrating that multi-dose administration regimens are equivalent or more active in their effects than a single administration of IMOM853 drug. The predicted mean serum concentration of the drug

IMOM853 administered once at 5.6 mg/kg IMOM853 was comparable to daily administration of the drug at 1.4 mg/kg for 3 days. Despite the presence of a lower total dose (4.2 mg/kg), the Cmax and area under the pharmacokinetic curve (АСо-54о) administration of the drug at a dose of 1.4 mg/kg for 3 days was compared with the antitumor activity in natural conditions (figure 11). These results suggest that maintaining a certain minimum concentration in blood plasma is critical for drug activity.

I00212| A weekly regimen of IMOM 853 matched with a total dose up to a single high dose of IMOM853 showed activity comparable to IP MIMO (Figure 12). Again, maintaining the mean plasma concentration above the minimum threshold required for drug activity with a single administration of IMOM853 (8.5 mg/kg) resulting in slightly higher SAD and AU but comparable to overall activity. The key difference in the predicted pharmacokinetic parameters with a single therapeutic effect compared to the multi-dose regimen is a sharp decrease in Stach. Stakh Pry

From the weekly regimen of the drug, according to forecasts, it will be almost 60,905, lower than Stakh with a single therapeutic effect of IMOM853. Since there is no apparent benefit to achieving a higher Cmax, avoiding higher plasma concentrations may be beneficial in reducing toxicity. 00213) It should be understood that the section "Detailed description of the essence of the invention" and the sections "Essence of the invention" and "Abstract" are intended to interpret the claims of the invention. In the sections "Gist of the invention" and "Abstract", one or more, but not all, examples of implementation options of the present invention are formulated by the inventor(s), and thus, they are not intended to limit the present invention and the appended claims of any how. (00214) This invention is described above with the help of functional building blocks illustrating the performance of the specified functions and their relationship. The boundaries of these functional building blocks in this document are defined arbitrarily for ease of description. Other limits may be defined, as long as the specified functions are properly performed and their relationships are maintained.

I00215| The foregoing description of specific embodiments will so fully disclose the general nature of the invention that others, using the knowledge of ordinary skill in the art, may readily modify and/or adapt such specific embodiments for various applications without undue experimentation, without departing from the scope of to him of this invention. Thus, such adaptations and modifications are within the scope of the invention and the range of equivalents of the disclosed embodiments of the invention, based on the description and instructions presented in this document. It should be understood that the phraseology or terminology in this document is used for purposes of description, but not limitation, such that the terminology or phraseology in this document should be interpreted by a skilled practitioner in light of the disclosure and guidance. (00216) The scope and context of the present invention should not be limited by any of the above-described exemplary embodiments of the invention, but should be defined only in accordance with the following claims and their equivalents.

SEQUENCES

ZEO IO Me:1 - human folate receptor 1

MAOSVMMTTOG PL UMUMAUMYaEAOTAVIAMAVTE AND MUSMMAKNNKEKROIREOKI NEOSARMUVKMAS

SZTMTZOEANKOUBZUI UVEMUMNSSEMARASKANEIOYUUTSI MESZRMI aRULOOMROBUUVKEVMI

MURISKEOSEOSMUMEOSAT5U TOCOMMUNKOIMUMUTZaeEMKSAMIaAASORENEMERTRTMI SMEM/T

NZUKUZMUZNazavsioMmUugrRAOSMRMEEMAVEMAAAMZYaASaRMAAMURNI BI A MO U 5

ЗЕО ІО Мо:2 - послідовність нуклеїнової кислоти людського рецептора фолату 1 аддсісадсдда(дасаасасадсідсідсісснсіаддіддддасюціадіададдаддсісадасааддандсадддоссаддасі дадсіїсісааідісідсаїдаасдссаадсассасааддаааадссаддссссдаддасаадносаїдадсадідісдасссіддада аадаадссідсюНсіассаасассадссаддаадсссаїааддацнссіассіаіаіїадансаасіддаассасідідчадачащда сассідссдсааасддсацшсаїссаддасассідссісіасдадідсісссссааснддоадсссіддаїссадсаддіддаїсададсі дасдсааададсдадіасідаасдідссссідідсааададдасідідадсаадддадаадандісдсассіссіасассідсаадад саасіддсасаадддсіддаасіддаснсадддашаасаадідсосадідддадсідссідссаасснссацсіасіссссасассс асюпнсідодсаацдааасіддасісасіссіасааддісадсаасіасадссдадддадіддссосідсаїссадацідднсдассса дсссадддсаассссааіїдаддаддаддсдадунсіаїдсідсадссададіддддсіддасссідддсадссіддссшссідснНадс сюдсссіаадсідсідіддсідсісадс

ZEO IO Me:Z - pimMom19 uNS

OMOI MOBIAEUMUKROaABUKIZSKABOM TE TOM EMMUUUKOZRYOBI EMO VINRURIOTHEUMOKROS

KATI TMOKZ5OZMTANMEGT 5I T5ZEORAUUU STA razvaMOUUuSsvattUTtU55

ZEO IU Me:4 - piMom19 mi Sm1.00

RIMGTO5RI 5I AUB ORAPZSKABOVUVEAITOI MNUUNOKROOSOORAP IMAVAZMI EADOMROVEZO

ZazKTOETI MIZRMEAESAATUUSOOZAEMRUTRSIITKI EIKA

ZEO IO Moe:5 - piMom19 mi Sm1.60

RIMGTO5RI 5I AUB ORAPZSKABOVUVEAITOI MNUUNOKROSORVI PIVAZMI EAEUMROVEZOa

About

ZEO IO Mo:6b - pimMom19 m S SOV1

KABOBUBEASTOI MN

ZEO IO Moe:7 - pimMom19 m C SOV2

VABZMI EA

ZEO IO Mo:8 - pimMom19 m IS SOVZ

OOBVEMRUT

ZEO IO Moe:9 - pimMom19 UNnS SOVI1

MEM

ZEO IO Mo:10 - piMom19 UNS SON - Determined according to Kabai

WINRUraYUTtTEUMOKROS

ZEO IO Mo:11 - piMom19 UNS SON - Determined according to Abt

WINRUROOTE

ZEO IO Mo:12 - piMom19 UNS SOVZ uUuravvAMOrU

ZEO IU Me:13 - sequence of amino acids pPIyMOom19 NS

OMOI MOBIAEUUKROABUKIZSKABOM TE TOM EMMUUUKOZRYOBI EMMA WINRMOSOTEMMOKEEOa

KATI TMOKZ5OZMTANMEGT 5I T5EORAU USTA UravvAMOUMUOSTtTTUTU5ZAZTKOaRBMUERI ARZB5 kZTZaastAAHasi MKOMERERUTUBMMZYiaAG T5aMNTERAMI O55S(01 51 55UMGURZBU ITOTMIS

MUMNKRUMHMTKMOKKMERKZSOKTNTSRRORARHEIGY SORBZUBI ERRKRKOTI MIZATREUTSUUMOM5

NEOREMKEMUUUramMEMMNMAKTKRAEEOMMZTUUVUUMI TM NOM MSKEUKSKUZMKAI RARIE

KTIZKAKEORAEEROMMTI RRVOEI TKMOM5I TOI UK EMRZOIAMEMEZMOOREMMUKTTRRMI 05 bo ravgg ki UrKZAMOOSMMUEZSZUMNEAI NMNUTOK5BI 5I ROK

ZEO IYUO Me:14 - piMom19 And Sm1.00

RIMG TORI BI AM5I a ORAPZSKABOZMZEAIaT5I MNIUNOKRIOOSORACI IMAAZBMI EDOMRONEba 5a5KTOETI MIZRMEAESAATUUSOOZAVEURUTraSOITkKkI EIKATMAARZMEIERRBOEOY Ka TABMUM

SP MMEMRAEAKMOMKMOMAG OBaMZOEZMTEOOBKOBZTUBI 551TI TI ZKAOMEKNKUMMASEMTNO

SI 5BRUTKSEMNSOES

ZEO IYUO Me:15 - piMom19 I Sm1.60

RIMG TORI BI AM5I a ORAPZSKABOZMZEAIaT5I MNIUNOKRIOOSORATSI IMAAZBMI EDOMRONEB

Za5KTOE TI TZRIEAEOAATUUSOOZAEURUTEOSIaItkKI EIKATMAARBMEIERRBOBOY KBatABUM

SI HMMEMRAEAKMOUMKMOMAG O5aM5OEVMTEOOOBKOBTUBI 551TI TI BKAOMEKNKUMASEMTNO

SI 5BRUTKSEMNSOES

ZEO IU Me:16 - tyMom19 u/NS SOV2 - Determined according to Kabai

WINRUIVaYUTtTEMMOMEKO

LIST OF SEQUENCES

"FOR KHIMuKmOvVEM; I;

KUTU, VOVEVT Z

ROM, ZO5E "Zk" SCHEMES OF APPLICATION OF IMMUNOCONJUGATE ANTICOVI "1305 50 PROCESSING OF EQUIS "iy" Б1БББ3О5 "и5й 013 TsNeov "1505 61888337 zhhiiii" 803-105 О8 "50" BANYA "Zi" 90345215О.0О4 Б "15" THEY "i1605 16 "MU" Batepzhty version 5.5 "ee "ih 83 hai" BILOK "155 He aiah "ah mee aia viv vka meh tvo tnk osiv bez oevy ev gay bets mai Ter Uvi 1 Z 10 ih

Aia ma! Uzi biu si Aa biv tvag ag 16 Aia Teo aia aga te U 00zhЖВ y 25 35 you fe) dap o Uudi Suk Meb Ah dia buye No No Buz own Bub VrRO siu z shcha 4x

Rgo Bin ahv Bu bez ni biv bij Su5 AB vgo tigr aga tsUu5 dev div shchi 5 50 tsu suv Beg TIR AshY tab Bek siv 016 Aa niv Buv Abo Udi bag otug 55 ve 5 that ces tug aga RMe dov ikr o Avap ni sukh biu biz mezh yia Ro dia sSu5 yah what em

Kuz Aha No RBe ii sat down OR Tvg buh beb tu obi sSukh 5vgorko Av that 05 TO ii-a bi Bo Toli biv oshiv Ua! Or biy bey yiv aka rukh FO AgZ ney ih vi

KNEU 120 125

Uvi you abi maii ho bvy sSukh uh 10 OR Suv biz biv o terotgtr biv that 135 140 zho Suz Aha tak obVg Tu TVe o Suh tsu begb oivp troni uh siu Tgv i50 555 150

AB Ter tpb oBEg bu Be aho sub sSukh Aza Uvi b1u iz ATa Suye biv 1655 i7o 175 hga vne nii RVE Tug o RPe Bho tTVK ogo Tvgomai ben sSuz Ai iv iv

Ivo 155 150 tvrotib nih deb tuye vu5 Udi Zeg Aa TUug Bag o AgU Biu vk stu Ag. what what 205

Su i1e biv Mmeb Tgruorpe Akr rko Aid biv zu ev vro Aa bin oii 2 «5 220

In JSC Ago Ve tuk Aa az Aa Mei 5es biu JSC B1U Bho ter AV 285 2 235 240

Aiv ts orgo ve Be you bek oizhu aia bez Met ev be) tv be sey ek 2 25 veg "0 0 "i y "giv DNE "Her" not artepe "Oh | Щ зеЧастсвас ооазечасваає асадевоста сісстієтаз чиооцеаос сага аоо Бо озаостсаех сзазЗаастоє зКоЗассяоо вас ссаекоа то сабозасасе ї25 зацевссяса зЗЗзалазасє зпассссова часавостоас зецавсаотО ссозесскоя 1 ащозаоаато сстосіосє тассазевсє доссазоазо сссвсазеда ас есає що стататацат тсзастоцдня ссастсоба заааєдасає стосстосав пецасаєсес 30о асссвиваса сстосстеєя соус сссвасстоз спцссстоачає ссвасавуєо 5 ассазпацет Фоасосазаце спас засосасссс китасазвов ОВС 321 сіаточез зазаєквіс ЄЗС тас зони пса са сао ай зм севассї сани таа свавесеєзса отоозадето єстоссайсс тТкжссатЕке 543 тасттсоссз сасссвстВк ста тосзахт паазестоза стсастсста сайвоссаВе 500 застасвсс заздоаоїва ссастоасатс сваЗатасоче сєсувесоває ссзодЗсзає БО сссвасуаой ан цах всустакось ослоссвтоа ФеоФфюсєю оссстуцв та псстацесЕе фескостево сс ссска зеостостає доастусеква is TT "3 "i" 318 "Kf" PROTEIN i i "ka artificial pusltdOVness "Oh cache NyMeUuta UNS "Don't sow in biv your UZhi sow zeg 01u Aa You Uvi Uvi) mue rRgo u A 1 5 vo i5

Wag ma! uh Hi6 Bek sSuz su div hek osiu tugo tve vve tvg ostu here

Be mei aAhy Tgou Ua? buh bij bek go biu bij ev vi bij Te oti 55 40 45 oiu ARYA Ite Ni wgo tug Azov Oiu Azy TVge Bra tuye Azy bij buh RNE shcha 55 BO tsiv siu Buz Aa tb ben Te UZ! or vuh ag obeg Aba TVgoAIya Ni that KE 75 shcha mei biv izhy iv; bek ben TVgobag sat b5r be AivV o Udi tTuk o tuk Suh 53 Cho z5

TNg Agoa tu av s1u 5 AKO ATya Me Br tuye tre oiu piv Tu tvg 100 405 ce ve Uai tvgoUudi ego cher 115 "a" and "vn ХХ "10" Protein "ВХ" fat pnestidaaniet kagoh "ai" vymo UKOSU AYU "Ob » a

Are you watching TV? biy bek wgo yo Zek obets Aia Uyi Zzheeb ev 01u 1 5 o 15 ziv ego at ii ii6 bve buh wuz aiy beg bi Heb wai beg bve Aa o zh a siu Tyg obekye re) Mek nyv To oTuk Mi biy was hgo bi bii bii rt dga eat this her tTug AgO Aiya ZagoAvva ate biv Azfa biu uzi go OR

Kk 55 5

Aha RNe Beye 5iUu Beg biu he obu TV OABr Ov TVg ram Ap Ti vek that that 75 ho

Rgo Udi sat down ATa drove Abo didy led TNg otut tuye Suv sip biy Bek Aha

VU a Zk oi tuye bko tTuv Te BI siu biu biUu Tk ovBub5 from zii ii Buv Aha what zach is "and I

"Eiyh Protein "her" ARTIFICIAL POPULARITY "a" VE" PiMoatiV ALL, BO "Oz 5

Aashe khiv in vec Tvgobiv z oBgo without healing) Afa ma! ego men FU i 5 TO 15 ip vgo a1v Her her beg Suz uyu Aa bvgobiv bag Ua! Beg vna Aa

Ka i h o 5 Z siu TE bag oive Me ni igrotuye Ni5 pip was rez o Ya1U biv bib bro 35 40 45

Aha svi ozen tiv tuk o Ago vid Zag dav geo biv Aish so! in th Ar

Co. 5

Aka BNe Zag biu beg o biu bek gu5 TVg OR RNe TV oge)otvg ziv Zag 7 75 BO

Wow! Bin ATa ii Ar oATA AT TNK otuk tuye Suh biiv biv Zag Ago 5 vo in biv tukovbo tuye tab rve slu BIU biu tat muh ven bij 31 uz Ag what 105 what "M: B "iv sov BIDE ! "213" Click sequence "va3x Vimomiya s SOKI "Oh 6 uz Aid ego bi" 5eb Uai bek RpE A15 biu Tak beg bi mes niya y 5 10 15 cheh 7 "2 yo "ei BILOK "AZYA" artificial sequence "Ei "ai 7

Aha viv bZek Ah em biz viv i x "05 in "5 Z "eiev VvILEK "her" Artificial consciousness "eh "ai" Vvmoi V m Sova

"00" V : viv 5iya hek aga bir Tu vro tuye Tak i 5 y "2105 Z dyk NNYA "vadam BILOK "va" Artificial pespidozniEt hozhi" VyMmoMEK UVS SVI "0" 5 si tu BBe Me Av 1 x "a "ii 4 "kiv ILYK "iy" Artificial consciousness

UYU: "aka" Nymochiv UNS Sr is defined according to Kavdye "nih o

ABZ Ii Ni Ko tTukK Ach siu dev TV RVE tugo AV SIYA gu Na dyin yi 5 ku; 15

BU

"M" her "am o hai BIiDaK: "her" Artificial pespidovniEt "vai" NiMOoMiV US SOIO with defined according to Ai "MN" 1

Aha zhiv niv hgo Tug Ar ob1u der o tTng vne y In 10 "ih 7 "sii With "o" Belok and y "Ka" Artificial follow-up "Ok y "ay" MNomozia UNS SBK "ZO her

TU AN Si bek aka Aid o mek yzo tTuk y 5 "a 13 "eii" av zeizzh BILOK. . and min" Shuchny pOosptidevNya is "VO

"ey poMmoUT5 NS "NN 15 siy Uzi bip ven ouai bin bak osiu Aiv biv Uvi UVI buye go bu dyin ii 5 ia 15

Bek UZhi Suk her back Suz Gu AT ego biu Tuk tt oRae tTne o siu tut 20 25 o

Rne Met abi o tgr Ua! Su bivoveg go sto bip 5ev sbi bi otgv o Ti1ye 35 cha 45 siu agu zhiv nih rgo tug der p1u Ascho TvE RBe TuUubB ap siy uh Rna 5 sha siy b5iUu buh Aiz TK rez tk Ua! Ar obu Be" Beg AB OTNg AV NIV 55 m 75 what

Uei biv av bez bek em tigobak dinner Or Re viv Uai Tug tuk Su 85 cha cheE

OAR TV. Tug dar eiu bek AgO Aza Me OR Tuk Ter osiUu biv o1u tvg

Lo0 105 KE tik omaii TV: Uvi bag bag AV ЗБг ТК o tsuz biu Rgo 5vg o UVi vBa Rgo

Kzh ve KV 125 ivo aYi rReo dec dec uv bev TVg bak oiiu bi Tvg aia aa svi "U 130 435 140 puz ve ma? sub AV TUR he rko sat down hgo uV! Te Uudii bek tgrodvy

What 55 what

Zeus bi viz bab tb beyes b1u UZH niv TVe vne vgo Ai3 UVT iets bij yiv5 170 175

Zag obeg bi vi tugo bag ben bek bek Mai Uvi Te Uudi vro Zegye ag

KIVI 155 ZO ego yivn bim tTvg oYATy tTvgotTuk Gi was Azh di Ap Mya buh RKO Zag 135 ay 205 ah otVg vuz Uai AkhroBuU5 Buv UVI bib Bho buh ben sSuz der uv TNE a 28 ko

Mi tv Sud r RKO was Bho Aia ego sat Be without BiUu biu rt bek ka vk "iz o

Uvi vBne svi be bo bho buh Rgo Muz Jo Tvg oyi mezh kiv Bag Agu ah 250 za ivVe vo bin uzi tTve Sub Uudi Ua? in dhr Wow! bek nih bi yo rgo

BO 285 and half May movement RVE ap TRrotue May OR biU Ua sib ha) niv AZp ATa tya «va: 85

Was TIGOSU5 RRO Aga biv bib bip Tug Aza bBes tig tuye weight Uzi Uvi 29a 295 she

Zav udi bi otve Uvi bvo niv biv AzhroTgro Se abBa BiU vuh Bi Tu 305 o 315 Z tsu Sub Kub mai Bek Azhp buh A1a ien ovo Aia Rgo ii6 BT buye TV 25 330 335

Ii ego mub5 AJ BU run bziy Rgo Aga biv vro biv Uvi tuye TVK orav o zach ZO

Rko Bgto bvgoago BYU biv Ben tab uh Aa biv Uuai bek omats tvg Suh 355 zo 355 vi az uz 5Tu pe TuUg rgo beg der her az haZ Bib ttvovits 5et

ЗО Zх 350 dep bi sip РРО BI dev j Tuk uvstne tve РРО ego Uudi Be Ar

Kz 295 Mshchyuyu zag Azy bi shcha vve vne rets o tug zagobuz gay tvg o Udi Ar obu Shag 305 30 5

Ata Ter osv biv bi Ah Ui RN ek sSukh bag Ua! meh nih Battle Aa

KU 425 Ben ry Ni dp than Tuk TNgosip" MKuz Zegoivy Bek ke zek Rgo schu Bu 440 А45 ke ii "eyelashes" 218 hoiin Protein "her" ytuka sequence "Io" hai" NymeUiV se 00 "ve I dav ha Uuai rez tk Zi Zev bro Sev Zeg her; aiz Uai bek bez bi and 5 her | i5 siy Rgo ATa liv ZE Zeg osukh suye Aia zek biy bek Ua! bek Ve Aid 2 25 za siu te obag rap me niz tgrotuye Ni s1y vuh RgOo bi bij bij Bho 35 40 45

Aha izhnokets ti TUK Aha Aa God oAba ben bi) dia stu uzi vko Ar

FOR

AgO RYE Begobiu bekobiu ev muz yibg o ahr Re tab bec dv tiv ek 5 ta 25 o;

Rgo Uvi Bim Aiz bib z5r AV Aa tng tuye Tuk sSukh biv bij bek Aga 85 dO 95 bij tuye ro tuye te oBNe b1u biU biu Tk Buv er bin Se uh Ag what 385 what

Tvg hUai diz dia Rko bek ouv) RNe IT vp Rgo Rg beb ar Bi ip 128 125 iets uz Zag opiu TVb AT bek ouai mmai Suh web ve Aa Ai Re tug more 135 iso in AK bin AV uz udi bip o Tgr buye mai ajr Aa Aa ben biv bee 145 1 155 1650 sim j bek siyu Zegomai Tk bi siyu Ahr o zeg Guz ABrobeye TVe i55 170 15

Tuk Berg ivm o hve bek TR ober TV oii bek vue aid ajr otu 1 Gu

MOT 155 of 90

KNIFE Guz ha tu Hades Szhe Sta Ua! VR ovi bij 1u idu Zeg Zve vro i85 sh oh waiii tTnk buh wat RN ahy dko biu stasu su 210 giv "ah 15 "em Protein | . "Yev" artificial past tense "Ж" "3" VyMaMZ su, BO ex 15

But that one? rez Tab biv zak Rgo iev bek fen Aia Uai ek bach biu i 5 io i5 sib vro aiy her 116 er osuv vue aid Zvg bii bab uv bab Red dv

B 25 ZO

Ziu ve bek obvo Meeb ni TeRrotuk Ni bij buye vko biju bij bij rgo i5 40 45

Aha vno ven Her6 tue AkO ATa 5eg Ahp vu siv Alya bi Uschi Rg A5B

BO dga be bek biu Bek ovi ego was Te Azo RVE TNK ben otvk tiv bek 55 o a shcha

Rez chai ich Aza b Av Aa Aa VK Tuk Tub Suz Biy Biy zagodio vh Zo Z5 ba tTug Rg Tk іVe ORNe bi ih Bim TVkK tsu vec bij yiv gruz Ag 100 5 o

Tvk Wow! ATa ATa Bgo ego uzi vne hi Ve vro ha bag dar biv yiv i2O 125 iem buh bek Biu TK o ATy Zag ouV! tai Sub er o iets Aey dep vBe Tuk nku Shcha5 14)

Bho Aga sii ATa buh uv ziv gr osukh uai AbroAvp ATa ve Fiy Bag 145 150 i5 159

FiU Ay Zag viv bish bek oUai TVE biv biv der obev buh Ar oBek tyr

Tug bag vi bek bek Te osets Tgoiem bek sub AT AJr o tTuv piv buh 1850 ii 190 viz rub chai tus AT Suh sid uzi TVae Ni siv yeiu beb beb bek ego 195 200 205

Wow! tTvg obu 5eg Re Abp AGRO TU oi sub ve ih "ah her "va 17 "her PROTEIN "More artificial posytdvnost "eh "zhi" MO NS OKO Z determined by Za

Aga tiv Nib Rgo Tug Abr biu dhrotVg RVE tug Ahp bij AB vne vuz 1 5 10 ih

Av

Claims (96)

FORMULA OF THE INVENTION 1. A method of treating a human patient who has BOI K1-expressing cancer, comprising administering to the patient an immunoconjugate that binds to a ROI KI polypeptide, the immunoconjugate comprising an antibody or an antigen-binding fragment thereof comprising a region of detection complementarity of SOC-II variable light chain (MI) in accordance with ZEO IU MO: 6, MI. SOV-2 in accordance with 5EO IU MO: 7, MI. SOK-3 in accordance with 5EO IU MO: 8, SOK-1 variable heavy chain (MN) in accordance with 5EO IU MO: 9, MN SOK-2 in accordance with ZEO IU MO: 11 and MN SOV-3 in accordance with 5EO IU MO: 12, and maytansinoid, and the indicated immunoconjugate is administered in a dose of b milligrams (mg) per kilogram (kg) of the adjusted ideal body weight (AIVUM) of the patient. 2. The method according to claim 1, in which МН-СОВ-2 contains the amino acid sequence ХЕО ИЯ МО: 10. 3. The method according to claim 1 or claim 2, in which the immunoconjugate is administered once every three weeks. 4. The method according to any one of claims 1-3, in which the antibody or its antigen-binding fragment contains a heavy chain variable domain that contains ZEO IU MO: 3, and a light chain variable domain that contains 5EO IU MO: 4 or 5EO IU MO:5. 5. The method according to any one of claims 1-4, in which the antibody or its antigen-binding fragment contains a heavy chain variable domain that contains ZEO IU MO: 3, and a light chain variable domain that contains 5EO IU MO:5. 6. The method according to any one of claims 1-5, in which the antibody contains(s) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by a plasmid deposited in the American Type Culture Collection (ATSC). as PTA-10772, and (i) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited in ATCC as PTA-10774. 7. The method according to any one of claims 1-6, in which the immunoconjugate contains 1-10 maytansinoid molecules. 8. The method according to any one of claims 1-7, in which the immunoconjugate contains 2-5 maytansinoid molecules. 9. The method according to any one of claims 1-8, in which the immunoconjugate contains 3-4 maytansinoid molecules. 10. The method according to any one of claims 1-9, in which maytansinoid is OMA. 11. The method according to any one of claims 1-10, in which the immunoconjugate contains a sulfo-5ROV linker. 12. The method according to any one of claims 1-11, in which the immunoconjugate contains OMA and an antibody that contains (His) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) as PTA-10772, and (ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited in the ATCC as PTA-10774, and in which OMA is connected to the antibody using sulfo-5ROV. 13. The method according to any one of claims 1-5, in which the immunoconjugate contains OMA and an antibody that contains (its) heavy chain containing the amino acid sequence according to ZEO IU MO: 13, and (its) light chain, containing the amino acid sequence according to 5EO IU MO: 15, and in which OMA is connected to the antibody using sulfo-5ROV. 14. The method according to any 3 claims 1-13, in which the immunoconjugate is formulated for intravenous administration. 15. The method according to any one of claims 1-14, in which the cancer is ovarian cancer. 16. The method according to claim 15, in which the ovarian cancer is epithelial ovarian cancer. 17. The method of claim 16, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 18. The method according to any one of claims 1-14, in which the cancer is peritoneal cancer. Zo 19. The method according to any one of claims 1-14, in which the cancer is endometrial cancer. 20. The method according to any one of claims 1-14, in which the cancer is uterine cancer. 21. The method according to any one of claims 1-20, in which the sample obtained from the patient's body shows the expression of ROI K1 as measured by the immunohistochemical method (INS). 22. The method according to claim 21, in which the sample has a color intensity of at least 1 hetero. 23. The method according to claim 21, in which the sample has a color intensity of at least 1 homo. 24. The method according to claim 21, in which the sample has a color intensity of at least 2 hetero. 25. The method according to claim 21, in which the sample has a color intensity of at least 2 homo. 26. The method according to claim 21, in which the sample has a color intensity of at least C hetero. 27. The method according to claim 21, in which the sample has a color intensity of at least C homo. 28. The method according to any one of claims 1-27, which further comprises administering a steroid to the patient. 29. The method according to claim 28, in which the steroid is dexamethasone. 30. The method according to any one of claims 1-17 and 21-29, in which the cancer is ovarian cancer and the administration results in a decrease in the level of CA125. 31. The method according to any one of claims 1-30, wherein the administration results in reduced toxicity. 32. The method according to claim 31, in which the toxicity is ophthalmic toxicity. 33. The use of an immunoconjugate that binds to the ROIK polypeptide in the manufacture of a medicinal product for the treatment of ROI K1-expressing cancer, and the immunoconjugate contains an antibody or its antigen-binding fragment that contains a site for determining the complementarity of SOC-II of variable lung chain (MI) in accordance with ZEO IU MO: 6, MI. BO SOV-2 in accordance with 5EO IU MO: 7, MI. SOK-3 in accordance with 5EO IU MO: 8, SOK-1 variable heavy chain (MN) in accordance with 5EO IU MO: 9, MN SOK-2 in accordance with ZEO IU MO: 11 and MN SOV-3 in accordance with 5EO IU MO: 12, and maytansinoid, and said drug is formulated to be administered at a dose of 6 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBUM). 34. Application according to claim 33, in which the MH SOC-2 contains the amino acid sequence EE IU MO: 10. 35. Use according to claim 33 or 34, in which the immunoconjugate is intended for administration once every three weeks. 36. Use according to any of claims 33-35, in which the antibody or its antigen-binding fragment contains a heavy chain variable domain that contains 5EO IU MO: 3, and a light chain variable domain that contains ZEO IU MO: 4 or 5EO IYUO MO: 5. 37. Use according to any one of claims 33-36, in which the antibody or its antigen-binding fragment contains a heavy chain variable domain that contains 5EO IU MO: 3, and a light chain variable domain that contains ZEO IUO MO: 5. 38. Use according to any one of claims 33-37, in which the antibody contains () a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATSC) as PTA-10772, and (ii) a light chain containing the same amino acid sequence as Its light chain amino acid sequence encoded by a plasmid deposited in ATCC as PTA-10774. 39. Use according to any one of claims 33-38, in which the immunoconjugate contains 1-10 maytansinoid molecules. 40. Use according to any one of claims 33-39, in which the immunoconjugate contains 2-5 maytansinoid molecules. 41. Use according to any one of claims 33-40, in which the immunoconjugate contains 3-4 maytansinoid molecules. 42. Use according to any one of claims 33-41, in which the maytansinoid is a YUMA. 43. Use according to any one of claims 33-42, in which the immunoconjugate contains a sulfo-5ROV linker. 44. Use according to any one of claims 33-43, in which the immunoconjugate contains an OMA and an antibody that contains(s) a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) as PTA-10772, and (ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited in the ATCC as PTA-10774, and in which OMA is connected to the antibody using sulfo-5ROV. 45. Use according to any one of claims 33-37, in which the immunoconjugate contains OMA and an antibody that contains (i) a heavy chain containing an amino acid sequence according to BEO IJOO MO: 13, and (ii) a light chain containing the amino acid sequence according to 5EO IJOO MO: 15, and in which the OMA is connected to the antibody by means of sulfo-5ROV. 46. Use according to any one of claims 33-45, wherein the immunoconjugate is formulated for intravenous administration. 47. Use according to any one of claims 33-46, wherein the cancer is ovarian cancer. 48. Use according to claim 47, in which the ovarian cancer is epithelial ovarian cancer. 49. The use of claim 48, wherein the ovarian cancer is platinum resistant, recurrent or refractory. 50. Use according to any one of claims 33-46, wherein the cancer is peritoneal cancer. 51. The use of any one of claims 33-46, wherein the cancer is endometrial cancer. 52. The use of any one of claims 33-46, wherein the cancer is uterine cancer. 53. Use according to any one of claims 33-52, in which the sample obtained from the body of the patient shows the expression of BOI K1 as measured by the immunohistochemical method (INS). 54. Use according to claim 53, in which the sample has a color intensity of at least 1 hetero. 55. Use according to claim 53, in which the sample has a color intensity of at least 1 homo. 56. Use according to claim 53, in which the sample has a color intensity of at least 2 hetero. 57. Use according to claim 53, in which the sample has a color intensity of at least 2 homo. 58. Use according to claim 53, in which the sample has a color intensity of at least C hetero. 59. Use according to claim 53, in which the sample has a color intensity of at least Z homo. 60. Use according to any one of claims 33-59, which further comprises administering a steroid to the patient. 61. Use according to claim 60, in which the steroid is dexamethasone. 62. Use according to any one of claims 33-49 and 53-61, wherein the cancer is ovarian cancer and the administration results in a decrease in the level of CA125. 63. Use according to any one of claims 33-62, wherein the administration results in reduced toxicity. 64. The use of claim 63, wherein the toxicity is ophthalmic toxicity. 65. A method of treating a human patient who has BOY MK1-expressing cancer, which includes administering to the patient an immunoconjugate that binds to the BOYK1 polypeptide, and the immunoconjugate contains 3-4 UM4-maytansinoids and an antibody that contains () a heavy chain containing the same amino acid sequence as the heavy chain amino acid sequence encoded by the plasmid deposited in the American Type Culture Collection (ATCC) as PTA-10772, and (ii) a light chain containing the same amino acid sequence as the His light chain amino acid sequence encoded by the plasmid deposited in ATCC as PTA-10774, in which OM4 maytansinoids are linked to antibody using sulfo-ZROV, and the immunoconjugate is administered at a dose of 6 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBMM) once every three weeks. 66. The method according to claim 65, in which the sample obtained from the patient's organism shows the expression of BOI K1 at least 2 hetero as measured by the immunohistochemical method (INS). 67. The method according to claim 65 or 66, in which the cancer is ovarian cancer. 68. The method according to claim 67, in which the ovarian cancer is epithelial ovarian cancer. 69. The method of claim 68, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 70. The method according to claim 65 or 66, in which the cancer is peritoneal cancer. 71. The method according to claim 65 or 66, in which the cancer is endometrial cancer. 72. The method according to claim 65 or 66, in which the cancer is uterine cancer. 73. The use of an immunoconjugate that binds to the ROIK polypeptide in the manufacture of a medicinal product for the treatment of BOI K1-expressing cancer, and the immunoconjugate contains 3-4 OMA4-maytansinoids and an antibody that contains () a heavy chain containing the same amino acid sequence as the amino acid sequence of the heavy chain encoded by the plasmid deposited in the American Type Culture Collection (ATCC) as PTA-10772, and (ii) a light chain containing the same amino acid sequence as the amino acid sequence of the light chain , which is encoded by a plasmid deposited in ATCC as PTA-10774, in which OUM4-maytansinoids are linked to an antibody by means of sulfo-5ROV, and the specified drug is formulated for administration at a dose of 6 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIVUM) of the patient once every three weeks. 14. The application according to claim 73, in which the sample obtained from the patient's organism shows the expression of ROG KI at least 2 hetero as measured by the immunohistochemical method (INS). 75. The use of claim 73 or 74, wherein the cancer is ovarian cancer. 76. Use according to claim 75, in which the ovarian cancer is epithelial ovarian cancer. 71. Use according to claim 76, in which the ovarian cancer is platinum-resistant, recurrent or Z0 refractory. 178. The use of claim 73 or 74, wherein the cancer is peritoneal cancer. 79. The use of claim 73 or 74, wherein the cancer is endometrial cancer. 80. The use of claim 73 or 74, wherein the cancer is uterine cancer. 81. A method of treating a human patient who has BOI CI-expressing cancer, which includes administering to the patient an immunoconjugate that binds to a ROI CI polypeptide, and the immunoconjugate contains 3-4 OM4-maytansinoids and an antibody that contains ( i) the variable domain of the heavy chain, which contains the ZEO IU MO: 3, and the (her) variable domain of the light chain, which contains the ZEO IU MO: 5, in which OUM4-maytansinoids are connected to the antibody by means of sulfo-5ROV, and the immunocon yugat is administered at a dose of 6 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBUM) once every three weeks. 82. The method according to claim 81, in which the sample obtained from the patient's organism shows the expression of BOI K1 at least 2 hetero as measured by the immunohistochemical method (INS). 83. The method according to claim 81 or 82, in which the cancer is ovarian cancer. 84. The method according to claim 83, in which the ovarian cancer is epithelial ovarian cancer. 85. The method of claim 84, wherein the ovarian cancer is platinum-resistant, recurrent, or refractory. 86. The method according to claim 81 or 82, in which the cancer is peritoneal cancer. 87. The method according to claim 81 or 82, in which the cancer is endometrial cancer. 88. The method according to claim 81 or 82, in which the cancer is uterine cancer. 89. Use of an immunoconjugate that binds to the ROIK polypeptide in the manufacture of a medicinal product for the treatment of BOY K1-expressing cancer, and the immunoconjugate contains 3-4 pMa maytansinoids and an antibody that contains () the variable domain of the heavy chain, which contains ZEO IU MO: 3, and (her) variable light chain domain which contains ZEO IU MO: 5, in which OUM4-maytansinoids are linked to an antibody by means of sulfo-5ROV, and said drug is formulated for administration in a dose 6 milligrams (mg) per kilogram (kg) of the patient's adjusted ideal body weight (AIBW) once every three weeks. 90. The application according to claim 89, in which the sample obtained from the patient's organism shows the expression of ROG KI at least 2 hetero as measured by the immunohistochemical method (INS). 91. The use of claim 89 or 90, wherein the cancer is ovarian cancer. for 92. Use according to claim 91, in which the ovarian cancer is epithelial ovarian cancer. 93. The use of claim 92, wherein the ovarian cancer is platinum resistant, recurrent or refractory. 94. The use of claim 89 or 90, wherein the cancer is peritoneal cancer. 95. The use of claim 89 or 90, wherein the cancer is endometrial cancer. 96. 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